bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–10–04
forty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
  2. A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.
  3. Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.
  4. Targeting CH25H restores p62-mediated α-synuclein clearance.
  5. Redox activation of ATG5 licenses autophagy upon nutrient restriction.
  6. Atg39-dependent nucleophagy and Atg40-dependent ER-phagy require the Apq12/Brr6/Brl1 complex.
  7. A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
  8. Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.
  9. Sequestosome 1 (SQSTM1/p62) at the nexus of genome integrity maintenance, proteostasis regulation and organellar homeostasis.
  10. deptor disruption induces axonal and behavioral abnormalities through altered cholesterol metabolism in zebrafish.
  11. Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.
  12. RABC1 regulates ER-phagy to maintain er homeostasis in plants.
  13. Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes.
  14. Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
  15. Keratinocyte Autophagy in Inflammatory Dermatoses: Mechanisms, Disease-Specific Programs and Therapeutic Opportunities.
  16. Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older Adults.
  17. Lysosomal multi-omics reveals altered sphingolipid catabolism associated with lysosomal dysfunction in the aging brain.
  18. α-Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux.
  19. SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
  20. BAG3 coordinates astrocytic proteostasis of Alzheimer's disease-linked proteins via proteasome, autophagy, and retromer interactions.
  21. Stepwise-coordinated polymeric nanoplatform enables traceless cytosolic protein delivery and autophagy blockade for enhanced tumor therapy.
  22. Molecular mechanism and potential role of mitophagy in breast cancer.
  23. Avobenzone induces intestinal injury by targeting ATG14 and impairing mitophagy.
  24. Lysosomal dysfunction in neurodegenerative disease.
  25. mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction.
  26. AZP2006 in Parkinson's disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex.
  27. From aggregate structure to disease trajectory: the role of the proteostasis network.
  28. Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.
  29. Proteostasis and ageing dissidence.
  30. PTEN-L inhibits mitophagy and GSDME-dependent pyroptosis via Parkin dephosphorylation.
  31. A lysosome-targeted dual-lock fluorescent probe based on synergistic pH/viscosity response for visualizing autophagy and tumor tissues.
  32. DEPP1 connects nutrient and oxygen availability to maintenance of muscle mass.
  33. Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets.
  34. Posttranslational Modifications of p62/SQSTM1 in Health and Disease.
  35. p38 MAPK-associated autophagic response restrains TLR4/MyD88 signaling in RT-treated macrophages.
  36. More than the 'master regulator of cytosolic proteostasis': new roles for HSF1 in promoting tissue health.
  37. Dietary CoQ10 Ameliorates Age-Related Megakaryocyte Dysfunction via COPS3-Mediated Activation of Autophagy.
  38. Huntingtin Aggregate-Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice.
  39. TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation.
  40. Yeast-Based High-Throughput Screening Platform for Identifying Modulators of Mitochondrial Protein Import.
  41. Cellular and systemic modifiers of alpha-synuclein proteostasis.
  42. Nitrate-responsive Sialin2 couples stress granule assembly and clearance to maintain neuronal homeostasis.
  43. Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.
  44. CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.
  1. Nat Commun. 2026 08 31. pii: 10359. [Epub ahead of print]17(1):
    Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
    Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.
      The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, studies employing a liver-specific genetic mouse model demonstrate that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, postprandial activation of hepatic mTORC1 requires dietary protein, which dictates the insulin-responsiveness of the pathway. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity, despite overt impairments in insulin and glucose homeostasis, and blocking hepatic AKT-TSC-mTORC1 signaling did not affect these metabolic phenotypes. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.
    DOI:  https://doi.org/10.1038/s41467-026-77216-6
  2. Nat Commun. 2026 08 31. pii: 10374. [Epub ahead of print]17(1):
    A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.
    Elisabeth Holzer, Justyna Sawa-Makarska, Daniel Bernklau, Julia Romanov, Martina Schuschnig, Sascha Martens.
      Autophagy degrades cellular material by sequestering it within autophagosomes, which form de novo from precursors called phagophores. Phagophore assembly and expansion require ATG9A-positive seed compartments, the lipid transfer protein ATG2A, and the class III phosphatidylinositol 3-phosphate kinase complex I (PI3KC3-C1). PI3KC3-C1 synthesizes phosphatidylinositol 3-phosphate (PI3P), a key lipid that drives downstream processes for phagophore expansion, including ATG8 lipidation. We find that ATG9A compartments contain only traces of phosphatidylinositol (PI), likely insufficient for efficient PI3P production or recruitment of PI3P-binding effectors. Nevertheless, ATG2A is recruited to these compartments and mediates lipid transfer, including PI, into them. Remarkably, even without detectable PI3P, ATG9A compartments are direct substrates for ATG8 lipidation, and ATG8 proteins themselves enhance ATG2A-mediated lipid transfer. In cells, ATG2A is essential for the appearance of PI3P on ATG9A compartments. Our findings support a model in which a lipid transfer-driven feedback loop activates ATG9A compartments for phagophore expansion.
    DOI:  https://doi.org/10.1038/s41467-026-77368-5
  3. Cell Death Differ. 2026 Sep 30.
    Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.
    Marco Ferniani, Irene Sambri, Tuong Huynh, Rossella Pennella, Gennaro Tufano, Niculin J Herz, Barbara Rossi, Antonella Iannaccone, Francesco Trepiccione, Alessia Calcagnì, Andrea Ballabio.
      Birt-Hogg-Dubé (BHD) and Tuberous Sclerosis (TSC) are inherited cancer syndromes associated with kidney cystogenesis and tumorigenesis and caused by mutations of the folliculin (FLCN) and TSC1/2 genes, respectively. We and others previously showed that Transcription Factors EB (TFEB) and E3 (TFE3) are the main drivers of the kidney phenotypes observed in mouse models of these conditions. These transcription factors are also responsible for the feedback hyperactivation of the mechanistic Target of Rapamycin Complex 1 (mTORC1), a known tumorigenic factor. This raises the question of whether TFEB/TFE3 exert their oncogenic activity by inducing mTORC1 or by mTORC1-independent pathways. To address this question, we generated kidney-specific mouse models in which we knocked out factors that differentially control mTORC1 and TFEB/TFE3, thus uncoupling their activities. Specifically, we generated three kidney-specific conditional knockout lines: (1) Depdc5-KO mice in which loss of GATOR1 activity leads to mTORC1 hyperactivation and TFEB/TFE3 inhibition, (2) RagC-KO mice in which TFEB/TFE3 are constitutively active and mTORC1 activity is partially inhibited due to impaired Rag heterodimer formation, and (3) Flcn/RagC double KO mice to test whether mTORC1 inhibition induced by RagC loss ameliorates the aggressive kidney phenotype of FLCN KO mice. Comparison between these models revealed that mTORC1 hyperactivation is a key driver of cystogenesis and tumorigenesis, while TFEB/TFE3 constitutive activation further enhances and accelerates pathology by establishing a transcriptional program that integrates metabolic and stress-response pathways. Together, our findings define an oncogenic mechanism by which both mTORC1 and TFEB/TFE3 hyperactivation cooperate in kidney tumorigenesis.
    DOI:  https://doi.org/10.1038/s41418-026-01881-9
  4. Trends Pharmacol Sci. 2026 Sep 28. pii: S0165-6147(26)00231-2. [Epub ahead of print]
    Targeting CH25H restores p62-mediated α-synuclein clearance.
    Gavin S Dawe.
      Astrocytes remove extracellular α-synuclein aggregates through p62-dependent autophagy, yet the factors limiting this defense remain unclear. Zhang and colleagues recently identified cholesterol 25-hydroxylase as an inducible negative regulator of p62-mediated clearance. Genetic suppression or a p62-derived decoy peptide reduced α-synuclein pathology in mouse models of Parkinson's disease.
    Keywords:  Parkinson’s disease; astrocytes; glial protein homeostasis; peptide therapeutics; selective autophagy
    DOI:  https://doi.org/10.1016/j.tips.2026.09.002
  5. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753803. [Epub ahead of print]
    Redox activation of ATG5 licenses autophagy upon nutrient restriction.
    Sanghee Shin, Ekaterina D Korobkina, Claudia Lennicke, Nils Burger, Bingsen Zhang, Haopeng Xiao, Yaoyu Wang, Jonathan J Petrocelli, Shelley M Wei, David Wood, Yu Lei, Xiaomei Zhang, Maria C Perez-Matos, Muneeb A Sharif, Jiuchun Zhang, Helena M Cochemé, William B Mair, Edward T Chouchani.
      Dietary restriction (DR) protects against metabolic disease, extends lifespan, and is associated with remodeling of tissue reactive oxygen species (ROS). ROS control biological adaptation through reversible oxidation of protein cysteines, yet the targets of DR-initiated redox signaling are unknown. Here we generate OxiDR, a tissue-resolved atlas of the cysteine redox proteome that quantifies oxidation state under DR. Rather than oxidizing the proteome broadly, DR selectively targets a high-amplitude set of cysteines in a tissue-specific manner, allowing systematic classification of biological processes subject to DR-mediated redox regulation. Among the cysteines most highly oxidized upon DR is Cys19 of the core autophagy protein ATG5. We show oxidation of Cys19 is required for ATG5-mediated autophagosome formation and for autophagy triggered by nutrient restriction in human cells and mice. Reversible oxidation of this cysteine promotes ATG5 binding to ATG10, thus forming the ATG5-ATG12 conjugate that lipidates LC3B/ATG8 and matures the autophagosome. In mice, loss of this redox switch prevents effective initiation of autophagy upon nutrient restriction, resulting in gross tissue pathology and rapid onset of mortality. The autophagic response to nutrient restriction is thus gated by oxidation of a single cysteine.
    DOI:  https://doi.org/10.64898/2026.09.23.753803
  6. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2620353123
    Atg39-dependent nucleophagy and Atg40-dependent ER-phagy require the Apq12/Brr6/Brl1 complex.
    Dongmei Liu, Shuliang Chen, Hua Yuan, Susan Ferro-Novick, Peter Novick.
      Autophagic degradation of parts of the nucleus (nucleophagy) and endoplasmic reticulum (ER-phagy) utilizes the selective autophagy receptors, Atg39 and Atg40, that link their target structures to the autophagy machinery. Here, we show that a complex of three proteins, Apq12, Brr6, and Brl1, is needed for both Atg39-dependent nucleophagy and Atg40-dependent ER-phagy. Apq12, Brr6, and Brl1 each have two transmembrane domains flanking a luminal region that contains an amphipathic helix. The Apq12/Brr6/Brl1 complex has been implicated in membrane remodeling during nuclear pore formation. While autophagosomal flux is unaffected by the loss of Apq12, Brr6, or Brl1, vacuolar delivery of outer and inner nuclear membrane proteins (Hmg1, Nvj1, and Src1), pan-ER proteins (Sec63 and Per33), and an ER tubule junction protein (Lnp1) is blocked. In apq12Δ cells, Atg39 and Atg40 receptors concentrate in puncta and associate with the autophagic machinery; however, their delivery to the vacuole is blocked. Atg39 puncta extend into the cytoplasm but fail to detach from the nuclear envelope (NE), suggesting a defect in membrane scission. Coimmunoprecipitation and crosslinking analysis indicate that Atg39 and Atg40 interact with the Apq12/Brr6/Brl1 complex. We propose that the membrane remodeling activity of the Apq12/Brr6/Brl1 complex is needed to release fragments of the NE and ER so they can be sequestered within autophagosomes for degradation.
    Keywords:  Apq12; Brl1; Brr6; ER-phagy; nucleophagy
    DOI:  https://doi.org/10.1073/pnas.2620353123
  7. Nature. 2026 Sep 30.
    A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
    Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.
      Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-026-11093-3
  8. CNS Neurol Disord Drug Targets. 2026 Sep 29.
    Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.
    Anushka Verma, Swatantra Kumar Singh Kushwaha, Neelottama Kushwaha, Sayantan Dutta, Parul Nigam.
      Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.
    Keywords:  Neuroinflammatory; autophagy; neurodegeneration; pathology.; receptors; therapeutic strategies
    DOI:  https://doi.org/10.2174/0118715273459017260922073618
  9. Biol Chem. 2026 Sep 29.
    Sequestosome 1 (SQSTM1/p62) at the nexus of genome integrity maintenance, proteostasis regulation and organellar homeostasis.
    Celina Hirschelmann, Prince Saforo Amponsah.
      Sequestosome 1 (SQSTM1 or p62) is a multi-domain protein that functions as a scaffold for aggregating proteins into cytoplasmic inclusions and mediating their turnover via selective autophagy. However, p62 is more than an autophagy scaffold or adaptor protein; it's linked with endo/exosomal protein trafficking and the ubiquitin proteasome system and, through its interactions with many different proteins, plays important roles in regulating cell signaling events (e.g., oxidative stress response). While its core functions are linked to proteostasis maintenance, p62 is also involved in proteostasis-independent mechanisms. In this review, we highlight the well-established role of p62 in selective autophagy in mammalian cells and harmonize known and emerging p62 functions under three main themes: proteostasis regulation, genomic integrity maintenance, and organellar homeostasis. We highlight some open questions on the potentially pivotal role of p62 in bridging these themes, which we believe would herald the next decade of research involving this versatile protein.
    Keywords:  aneuploidy; genomic integrity; mitochondria; organellar homeostasis; proteostasis; sequestosome 1 (SQSTM1/p62)
    DOI:  https://doi.org/10.1515/hsz-2026-0146
  10. Neurobiol Dis. 2026 Sep 29. pii: S0969-9961(26)00378-5. [Epub ahead of print]230 107632
    deptor disruption induces axonal and behavioral abnormalities through altered cholesterol metabolism in zebrafish.
    Mingshan Zhou, Cuizhen Zhang, Gang Peng.
      The mechanistic target of rapamycin (mTOR) signaling pathway is a highly conserved regulator of cellular growth and survival. DEPTOR serves as an endogenous inhibitor of this pathway by directly binding to both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). While DEPTOR is extensively implicated in oncology and peripheral metabolism, its role in the nervous system remains poorly understood. In this study, we utilized CRISPR/Cas9 technology to disrupt deptor in the zebrafish model to investigate its neurodevelopmental functions. We found that deptor-/- larvae exhibit motor deficits alongside structural axonal abnormalities, characterized by misaligned and broadened axonal tracts. These phenotypes were accompanied by the transcriptional dysregulation of key cholesterol-regulatory genes and progressive, aberrant accumulation of cholesterol from 5 to 10 days post-fertilization. Pharmacological elevation of cholesterol levels recapitulated these axonal and behavioral defects in wild-type larvae, whereas clearance of excess cholesterol successfully rescued the mutant phenotype. Together, our findings demonstrate that deptor deficiency drives cholesterol dysregulation, causing structural and functional abnormalities in the nervous system. This study uncovers a novel link between DEPTOR, lipid homeostasis, and neurodevelopment, highlighting cholesterol metabolism as a potential therapeutic target for neurological disorders associated with mTOR pathway dysfunction.
    Keywords:  Axonal tract; Cholesterol; DEPTOR; SREBP-2; mTOR
    DOI:  https://doi.org/10.1016/j.nbd.2026.107632
  11. bioRxiv. 2026 Sep 25. pii: 2026.09.23.753918. [Epub ahead of print]
    Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.
    Mathew B McDougal, Abigail Sandoval, Mike Kinter, Antrix Jain, Sukyeong Lee, Sung Yun Jung, Wan Hee Yoon.
      We previously discovered that a de novo variant p.R528W in ATAD3A , encoding a mitochondrial membrane-anchored protein, causes a human neurological syndrome. While ATAD3A mutations induce aberrant lysosomal expansion accompanied by undigested material in the lysosomes, how mutant ATAD3A disrupts lysosomal homeostasis and whether this contributes to neurodevelopmental defects remain unknown. Here we show that pathogenic ATAD3A p.R528W expression disrupts the mTORC1-TFEB axis as revealed by dysregulation of mTORC1 substrate phosphorylation, TFEB nuclear localization, and CLEAR gene activation associated with lysosomal biogenesis. ATAD3A binds to lysosome-localized Rag C/D GTPases, which constitute a platform for TFEB recruitment, with pathogenic variants increasing this association and thereby decreasing lysosomal localization of Rag GTPases. Importantly, overexpression of RagC or RagD restores TFEB phosphorylation in human cells expressing p.R528W, and RagC- D overexpression or TFEB/Mitf knockdown rescues lysosomal expansion and neurodevelopmental defects in Drosophila . These data indicate that disrupted Rag GTPase recruitment to lysosomes and subsequent aberrant TFEB/Mitf activation contribute to neurodevelopmental and lysosomal phenotypes caused by pathogenic mutations in ATAD3A . Our work reveals a novel role for the mitochondrial resident protein ATAD3A in modulating lysosomal homeostasis through regulation of the mTORC1-TFEB axis, providing a mechanistic link between impaired mitochondrial and lysosomal homeostasis in a neurodevelopmental disorder.
    DOI:  https://doi.org/10.64898/2026.09.23.753918
  12. Autophagy. 2026 Sep 28.
    RABC1 regulates ER-phagy to maintain er homeostasis in plants.
    Shuai Hu, Xiaohui Ma, Zhengjia Wang, Jinbo Shen.
      Endoplasmic reticulum (ER)-phagy is an important ER quality-control pathway that selectively removes misfolded or unfolded proteins and damaged ER membranes through autophagic degradation in the vacuole. Recent studies have identified small guanosine triphosphatases (GTPases) as important regulators of the autophagy pathway. However, how they couple stress signals to ER-phagy remains poorly understood in plants. Our recent work demonstrated that RABC1 regulates ER-phagy under dithiothreitol (DTT)-, tunicamycin (TM)-, and heat-induced ER stress through interaction with the exocyst complex component SEC5A. Upon ER stress, green fluorescent protein (GFP)-RABC1 was recruited to the ATG8e-positive autophagosomes from the ER and Golgi in root cells, whereas autophagic flux and calnexin 1 (CNX1)-mRFP-tagged ER membranes turnover were impaired in the rabc1 mutant. Together, our findings support a model in which RABC1 acts as a molecular switch that interacts with distinct effectors to regulate autophagy under different stress conditions.
    Keywords:  Autophagy; Er-phagy; RABC1; SEC5A; er stress
    DOI:  https://doi.org/10.1080/15548627.2026.2739788
  13. bioRxiv. 2026 Sep 26. pii: 2026.09.25.754437. [Epub ahead of print]
    Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes.
    Mehdi Dianatpour, Dipanjan Banerjee, HyunKyung Kim, Jiyoung Moon, Rui Zhu, Hang Zhou, Arpita Neogi, Trojan Rugira, Shrikant Mane, Adebowale Adeniran, Brisa Paliuqi, Ho-Joon Lee, Lucila Ohno-Machado, Arya Mani.
      Residual cardiovascular risk persists despite lipid-lowering therapy, independent of LDL and Lp(a), reflecting cholesterol dysregulation. We identify STARD9, a lysosomal cholesterol-sensing kinesin, as a causal gene for divergent familial dyslipidemias and premature atherosclerosis. Its START domain binds cholesterol to govern lysosomal positioning. Rare variants segregate with autosomal dominant hypercholesterolemia and premature coronary disease, while common variants associate with reduced HDL and elevated triglycerides. Both converge on lysosomal cholesterol sequestration, ER depletion, mTORC1 SREBP2 activation, impaired autophagy, and NF-kB inflammation, yet diverge through opposite lysosomal positioning: the rare variant disperses lysosomes peripherally, phenocopying START domain loss across cholesterol sequestration, lysosomal positioning, and TFEB activation, triggering LDLR degradation and CASM/TFEB-dependent efflux that preserves HDL, whereas the common variant causes perinuclear retention that suppresses TFEB dependent lipid-handling transcripts, yielding hypertriglyceridemia and low HDL. In Stard9-knockout mice, enterocyte cholesterol sequestration drives SREBP2 dependent NPC1L1 upregulation and apical localization, increasing intestinal cholesterol absorption. These findings position lysosomal cholesterol trafficking as a targetable node in statin-refractory cardiovascular disease.
    DOI:  https://doi.org/10.64898/2026.09.25.754437
  14. bioRxiv. 2026 Sep 24. pii: 2026.09.01.748489. [Epub ahead of print]
    Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
    Lily A Gates, Dustin C Bagley, Konstantinos Kalyviotis, John Fadul, Tania Auchynnikava, Maria Voronkov, Jody Rosenblatt.
      During homeostasis, crowded cells with the lowest energy levels are eliminated by extrusion via Piezo1 signalling to maintain constant cell numbers. However, crowding-induced extrusion does not necessarily remove damaged or otherwise unfit cells. Here, we show that glucose or glutamine starvation triggers a rapid, regulated wave of extrusion, called starvation-induced cell extrusion (STICE), that selectively eliminates cells bearing DNA damage markers via a p53-dependent, Piezo1-independent pathway, improving monolayer fitness. Unlike non-extruding cells, which recycle contents through autophagy and lysosomal digestion, p53-activated cells instead use LC3 to drive lysosomal exocytosis, promoting extrusion signalling. By eliminating defective and transformed cells, STICE confers resistance to damage and apoptotic stimuli in the remaining monolayer. STICE thus acts as a tissue-level analogue of autophagy: rather than improving individual cells by digesting and recycling damaged components, it improves tissue fitness by eliminating substandard cells.
    DOI:  https://doi.org/10.64898/2026.09.01.748489
  15. Exp Dermatol. 2026 Oct;35(10): e70370
    Keratinocyte Autophagy in Inflammatory Dermatoses: Mechanisms, Disease-Specific Programs and Therapeutic Opportunities.
    Yulu Wang, Kevin M Truong-Balderas, Yi Gao, Claudia Lasalle, Sabrina Schundler, Bethany E Perez White, Kyle T Amber, Adrian P Mansini.
      Autophagy is increasingly recognised as a regulator of epithelial stress adaptation in the skin, but its role in inflammatory dermatoses remains difficult to interpret because autophagy intersects with barrier biology, keratinocyte differentiation, immune signalling, intracellular trafficking and lysosomal degradation. Keratinocytes are immune-competent epithelial cells that integrate cytokine exposure, oxidative stress, microbial sensing and tissue injury into inflammatory output. In this review, we synthesize evidence on keratinocyte autophagy as a disease-dependent regulator of epidermal homeostasis and cutaneous inflammation. We summarize core autophagy machinery, selective autophagy programs relevant to epidermal differentiation and the interpretive value of autophagic flux and lysosomal competence. We then discuss how autophagy influences keratinocyte differentiation, organelle clearance, lipid handling, barrier support, inflammatory restraint and stress adaptation. Disease-specific evidence is reviewed in psoriasis, AP1S3-associated pustular autoinflammation, atopic dermatitis and vitiligo. Across these settings, keratinocyte autophagy cannot be classified as uniformly protective or pathogenic; its effects depend on inflammatory context, trafficking state, cell-type-specific outputs and the ability of lysosomes to complete degradation. We also consider lessons from other barrier epithelia, therapeutic implications and common methodological limitations. A keratinocyte-centered, flux-aware interpretation provides a framework for organizing disease-specific autophagy biology and for designing more rigorous mechanistic studies in inflammatory dermatoses.
    Keywords:  atopic dermatitis; autophagic flux; keratinocytes; lysosomal function; psoriasis; vitiligo
    DOI:  https://doi.org/10.1111/exd.70370
  16. Aging Cell. 2026 Oct;25(10): e70734
    Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older Adults.
    Tatiana M Moreno, Stephanie R Heimler, Ryan J Moran, Hava Shoshana Barkai, Lina Scandalis, Larissa Traxler, Ashley Neil, Stephen Dozier, Jaclyn Bergstrom, Alexandre R Colas, Sanjeev S Ranade, Anne G Bang, Jerome Mertens, David Wing, Anthony J Molina, Caroline Kumsta.
      Autophagy is widely proposed to decline with age; however, direct evidence across human cell types remains limited. Moreover, it is unclear whether age-associated changes in autophagy-gene transcription are accompanied by corresponding changes in autophagic activity, and whether autophagic activity relates to physiological function during aging. We performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort. Autophagy-related gene expression increased with age in primary dermal fibroblasts and, to a lesser extent, in induced neurons (iNs). However, autophagy flux was cell type- and sex-specific and uncoupled from transcriptional remodeling. Autophagy flux decreased in male fibroblasts, remained stable in female fibroblasts, and increased in female iNs with age. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became increasingly heterogeneous with age and trended higher in older individuals, independent of sex. Associations between autophagy flux and physiological function varied across the adult lifespan; however, in adults aged > 70 years, higher autophagy flux was associated with reduced physical function. In a pilot intervention study, PBMC autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function, suggesting that autophagic activity in PBMCs is responsive to physiological intervention in late life. Together, these findings show that autophagy is remodeled in a cell type-, sex- and physiological function-dependent manner during aging, challenge the view that autophagy uniformly declines with age, and suggest that elevated autophagy flux in older adults may reflect compensatory responses to age-associated stress rather than enhanced autophagic capacity.
    Keywords:  aging; autophagy; direct conversion; exercise; human primary dermal fibroblasts; induced neurons (iNs); peripheral blood mononuclear cells (PBMC)
    DOI:  https://doi.org/10.1111/acel.70734
  17. Cell Rep. 2026 Oct 01. pii: S2211-1247(26)01144-7. [Epub ahead of print]45(10): 118065
    Lysosomal multi-omics reveals altered sphingolipid catabolism associated with lysosomal dysfunction in the aging brain.
    Chinmoy Sarkar, Yi Chen, Dexter Ph Nguyen, Mehari M Weldemariam, Yulemni Morel, Amir Mehrabani-Tabari, Nikki Gorny, Olivia Pettyjohn-Robin, Nivedita Hegdekar, Sagarina Thapa, Sazia Arefin Kachi, Sabrina Bustos, Stephanie Zalesak-Kravec, Christina Williams, Nicholas Leahy, Renee Ti Chou, Shilpa D Kumar, Carrie McCracken, Thomas A Blanpied, Mariusz Karbowski, Jace W Jones, Maureen A Kane, Michael P Cummings, Marta M Lipinski.
      Lipids dynamically reside in multiple intracellular locations, and their organellar distribution is important for function. During brain aging, lysosomal lipid changes have been noted, but lipid identity, interactions, and functional relevance have not been characterized. We used mass spectrometry to assess longitudinal changes in the lipidome and proteome of lysosomal fractions from the murine cortex, from 3 to 24 months, followed by multi-omics factor analysis (MOFA) to identify factors underlying lysosomal aging. Our data uncover an age-dependent increase in lysosomal abundance of lipid and protein myelin components and suggest altered sphingolipid catabolism favoring degradation of sphingomyelins over glycosphingolipids. We experimentally corroborate MOFA predictions to demonstrate that age-dependent accumulation of myelin-derived glycosphingolipids is associated with lysosomal enlargement and dysfunction and is most pronounced in microglia. Our findings suggest that age-related lysosomal lipidome changes resemble those observed in lysosomal storage diseases and underscore the importance of organelle-specific analyses for elucidating lipid function.
    Keywords:  CP: metabolism; CP: neuroscience; autophagy; brain aging; glycosphingolipids; lipid metabolism; lysosomes; mass spectrometry; microglia; multi-omics factor analysis (MOFA); myelin
    DOI:  https://doi.org/10.1016/j.celrep.2026.118065
  18. Aging Cell. 2026 Oct;25(10): e70713
    α-Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux.
    Mengting Qin, Xuying Xiang, Xiaoqing Guo, Shengnan Wang, Jiaojiao Chen, Dailiang Jiang, Yuhang Feng, Jiangnan Yu, Ling Mao.
      Atherosclerosis, recognized as a prototypical age-associated vascular disease, is driven by macrophage foam cell formation. Individuals with Parkinson's disease (PD) exhibit an elevated risk for stroke. While α-synuclein (α-Syn) is known for its neuronal role in PD, its presence in the circulation and potential vascular effects remain unexplored. Here, we identify α-Syn as a previously unrecognized circulating factor that promotes atherosclerosis. α-Syn was detected in human atherosclerotic plaques. Genetic deletion of α-Syn reduced atherosclerotic lesion size and macrophage lipid accumulation in a mouse model of atherosclerosis induced by overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9). On the contrary, administration of exogenous α-Syn accelerated atherosclerosis in Apolipoprotein E knockout (Apoe-/-) mice. Mechanistically, α-Syn promoted macrophage foam cell formation by impairing autophagic flux, accompanied by activation of PI3K-mTOR signaling. Proteomic analysis identified the membrane raft protein flotillin-1 (FLOT1) as a candidate upstream mediator. Flot1 knockdown reduced α-Syn internalization, PI3K phosphorylation, autophagy impairment, and lipid accumulation, while pharmacological inhibition of PI3K or mTOR attenuated the effects of α-Syn. Together, these findings identify a FLOT1-associated pathway through which extracellular α-Syn disrupts macrophage autophagy and promotes atherosclerosis.
    Keywords:  FLOT1; atherosclerosis; autophagy; α‐Synuclein
    DOI:  https://doi.org/10.1111/acel.70713
  19. Nat Commun. 2026 09 11. pii: 10407. [Epub ahead of print]17(1):
    SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
    Ke Hu, Yin-Hu Wang, Anthony Y Tao, Maxwell McDermott, Miki Jishage, Li Zhong, Thomas Boehringer, Marcus J Hines, Sergei B Koralov, Ebbe Boedtkjer, Stefan Feske.
      Antibody-producing plasmablasts (PB) and plasma cells (PC) are critical for humoral immunity, autoimmunity and vaccine responses. Despite the importance of environmental stressors in regulating humoral immune responses, the influence of pH on PB and PC differentiation remains elusive. Here, we identify SLC4A7/NBCn1, a Na+/HCO3- cotransporter, as a selective regulator of PB differentiation in vitro. SLC4A7 deletion also impairs the formation of antibody secreting cells (ASCs) and antibody responses in mice in vivo following immunization and influenza A virus infection. Mechanistically, SLC4A7 deletion results in intracellular acidification and lysosomal alkalinization, and is associated with impaired function of the mechanistic target of rapamycin complex 1 (mTORC1). Enforcing mTORC1 activation in SLC4A7-deficient B cells or B cells in which intracellular pH is acidified by blocking Na+/H+ exchanger (NHE) function restores PB differentiation in vitro. Moreover, ASC differentiation and antibody responses are impaired under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Altogether, we identify a critical relationship between intracellular pH regulation through SLC4A7 and mTORC1-dependent ASC differentiation and humoral immunity.
    DOI:  https://doi.org/10.1038/s41467-026-77588-9
  20. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2528514123
    BAG3 coordinates astrocytic proteostasis of Alzheimer's disease-linked proteins via proteasome, autophagy, and retromer interactions.
    Zachary M Augur, Garrett M Fogo, Courtney R Benoit, Masin A Kearney, Gizem Terzioglu, Zachary R Murphy, Mason R Arbery, Natacha Comandante-Lou, Duc M Duong, Nicholas T Seyfried, Philip L De Jager, Tracy L Young-Pearse.
      Bcl-2-associated athanogene 3 (BAG3) is a mediator of chaperone-assisted selective autophagy, and in the brain, is most highly expressed in astrocytes. However, its role in astrocytes remains poorly defined. Given the genetic and pathological links of BAG3 to proteostasis and neurodegenerative diseases, we investigated how BAG3 contributes to astrocyte function and Alzheimer's disease (AD). To define its function and relevance, we used single-nucleus RNA sequencing to confirm BAG3 enrichment in astrocytes and employed CRISPR/Cas9 editing of human induced pluripotent stem cells followed by proteomic and transcriptomic profiling, which revealed that BAG3 loss caused greater disruption in astrocytes than in neurons. BAG3-deficient astrocytes displayed reduced autophagy, lysosomal abundance and activity, and proteasome function. Coimmunoprecipitation identified BAG3 known binding partners (e.g., HSPB8, proteasome regulators), as well as an interactor in the retromer complex, VPS35. BAG3 deficiency resulted in altered retromer activity as measured by amyloid precursor protein (APP) localization in endosomes. In addition to validating these binding partners, integrative -omics analyses showed that BAG3 regulates AD-relevant proteins (GFAP, BIN1), as well as HSPB8. Functionally, BAG3 knockout astrocytes exhibited impaired amyloid-β proteostasis when cocultured with APP/PSEN1 mutant neurons, directly linking BAG3 to a disease-relevant astrocyte phenotype. Finally, analysis of postmortem human brain revealed that BAG3 expression marks a stress-responsive astrocyte subtype in aged individuals. Together, these findings demonstrate that BAG3 coordinates astrocyte proteostasis through interactions with regulators of autophagy, proteasome activity, and retromer function, positioning it as a potential therapeutic target and central node of astrocytic protein quality control in neurodegeneration.
    Keywords:  Alzheimer’s disease; BAG3; astrocytes; autophagy; iPSC
    DOI:  https://doi.org/10.1073/pnas.2528514123
  21. Natl Sci Rev. 2026 Sep;13(18): nwag446
    Stepwise-coordinated polymeric nanoplatform enables traceless cytosolic protein delivery and autophagy blockade for enhanced tumor therapy.
    Peng Zhang, Yaowei Zhu, Hongyu Zhang, Shuai Tang, Zhihui Guo, Xuan Yi, Chunsheng Xiao, Xuesi Chen.
      Autophagic degradation of proteins following cellular internalization and endosomal escape presents a significant, yet underexplored, challenge in intracellular protein delivery. This highlights the need for delivery carriers capable of concurrently achieving cytosolic delivery and autophagy inhibition. Here, we report a stepwise-coordinated polymeric nanoplatform based on a tailor-made amphiphilic triblock copolymer (mPEG-b-PGBA-b-PGCQ) that enables traceless cytosolic delivery of functional proteins while concurrently suppressing autophagy. This system incorporates three modular blocks: an mPEG stealth shell, a PGBA block for reversible protein conjugation via pH-sensitive iminoboronates, and a PGCQ block grafted with autophagy inhibitor hydroxychloroquine (HCQ) via self-immolative disulfide linkages. Using ribonuclease A (RNase A) as a model therapeutic, we demonstrated efficient protein release in acidic endolysosomes, simultaneous HCQ-promoted endosomal escape, and glutathione-triggered HCQ liberation in cytosol. The released HCQ significantly enhanced RNase A-induced apoptosis by inhibiting both the autophagic degradation of the protein and RNase A-induced mitophagy. Furthermore, by integrating cytosolic delivery with autophagy inhibition, this platform produced notable functional enhancement across multiple proteins, including green fluorescent protein, β-galactosidase, and horseradish peroxidase, demonstrating its broad utility. Our work establishes a potent traceless delivery and autophagy-blockade strategy for boosting intracellular protein efficacy, with considerable potential in both basic research and biomedical applications.
    Keywords:  autophagy blockade; polymer nanocarrier; protein delivery; protein drug; tumor therapy
    DOI:  https://doi.org/10.1093/nsr/nwag446
  22. J Cancer. 2026 ;17(10): 1808-1820
    Molecular mechanism and potential role of mitophagy in breast cancer.
    Xin Yang, Youqin Zeng, Ling Zhang, Yuting Ye, Siyu Chen, Changyou Wei, Ping Leng.
      Breast cancer remains the most commonly diagnosed malignancy among women worldwide and a leading cause of cancer related mortality in this population. Mitochondrial dysfunction is increasingly recognized as a hallmark of breast cancer, contributing to tumor initiation, progression, and therapeutic resistance. Mitophagy, a selective form of autophagy that eliminates damaged or dysfunctional mitochondria, is essential for maintaining cellular and mitochondrial homeostasis. Accumulating evidence indicates that mitophagy plays a context dependent role in breast cancer. Impaired mitophagy permits the accumulation of damaged mitochondria and promotes tumor growth, migration, and invasion, whereas appropriately activated mitophagy removes damaged mitochondria and suppresses tumor progression. This review synthesizes the molecular mechanisms of mitophagy, its crosstalk with ferroptosis, and its context dependent roles in breast cancer development, with the aim of offering therapeutic insights that may inform breast cancer treatment.
    Keywords:  breast cancer; cell death; mitophagy; therapy
    DOI:  https://doi.org/10.7150/jca.140132
  23. Cell Commun Signal. 2026 Sep 10. pii: 514. [Epub ahead of print]24(1):
    Avobenzone induces intestinal injury by targeting ATG14 and impairing mitophagy.
    Zi-Kang Gui, Zi-Jia Huang, Xiao-Yu Qi, Bao-Peng Wang, Jian-Rui Zhong, Yu-Jie Zeng, Yi-Ping Zhou, Qing-Yu He, Jing Zhang, Yang Wang.
       BACKGROUND: Avobenzone (Avo) is a widely used ultraviolet filter in sunscreens and facial skincare products. In addition to dermal exposure, chronic oral intake may also occur through daily-use products. However, the potential intestinal toxicity of Avo and its underlying mechanisms remain poorly understood.
    METHODS: We investigated the intestinal effects of Avo using repeated oral exposure mouse models, the Caco-2 intestinal epithelial cell line, human intestinal organoids, proteomic analysis, and mechanistic assays examining autophagy, mitophagy, mitochondrial stress responses, and Wnt/β-catenin signaling.
    RESULTS: Administration of Avo (10-40 mg/kg) for two months induced intestinal epithelial injury in mice, as evidenced by reduced crypt number, shortened villi, impaired intestinal epithelial barrier, and decreased intestinal stem cell abundance. Avo also caused mitochondrial dysfunction, oxidative stress, and lipid accumulation. Mechanistically, Avo interacted with ATG14, a key component of the autophagy initiation complex, and promoted CUL3-mediated ubiquitination and proteasomal degradation of ATG14. Loss of ATG14 impaired mitophagy, leading to the accumulation of damaged mitochondria and activation of eIF2α-ATF5-associated mitochondrial unfolded protein response (UPRmt). This mitochondrial stress suppressed Wnt/β-catenin signaling, reduced maintenance of LGR5-positive intestinal stem cells, and ultimately disrupted epithelial regeneration. Importantly, pharmacological induction of autophagy with rapamycin or inhibition of stress signaling with ISRIB alleviated Avo-induced intestinal injury in mice. Similar effects were observed in human intestinal organoids.
    CONCLUSIONS: These findings identify a previously unrecognized intestinal toxicity associated with Avo exposure and suggest that disruption of ATG14-dependent mitophagy and mitochondrial quality control is a key mechanism underlying this effect.
    Keywords:  ATG14; Avobenzone; Intestinal organoid; Mitophagy; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1186/s12964-026-03211-5
  24. Nat Rev Neurol. 2026 Sep 29.
    Lysosomal dysfunction in neurodegenerative disease.
    Sarah M Brooker, Robert Coukos, Dimitri Krainc.
      Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.
    DOI:  https://doi.org/10.1038/s41582-026-01262-3
  25. CNS Neurosci Ther. 2026 Oct;32(10): e71174
    mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction.
    Yang Zou, Jun Yang, Yang Li, Guodong Wang, Wen Lu, Xiaoping Chen, Xingxing Ma, Kehan Chen, Peng Liang, Yinghui Wu, Tao Zhuo.
       BACKGROUND: Although depression is a potent risk factor for Alzheimer's disease (AD), the underlying causal mechanisms remain unclear. This study investigated the molecular and circuit-level mechanisms linking chronic stress to accelerated AD pathogenesis and evaluated the therapeutic potential of precise mTORC1 targeting.
    METHODS: A chronic restraint stress (CRS) paradigm was established in 5xFAD mice. Multi-scale neurofunctional and histopathological alterations were deconstructed using behavioral profiling, wide-field and two-photon calcium imaging, immunofluorescence, and bulk RNA-sequencing. Pharmacological intervention was conducted using the specific mTORC1 inhibitor EN6.
    RESULTS: CRS severely impaired cortical slow-wave oscillations and induced aberrant prefrontal single-neuron hyperactivity, exacerbating cognitive decline. These network deficits were accompanied by accelerated AD hallmarks, including elevated Aβ deposition, dystrophic neurite aggravation, and reactive gliosis. Mechanistically, transcriptomic profiling and biochemical validation revealed that chronic stress suppresses autophagic pathways via selective hyperactivation of mTORC1 signaling rather than the AMPK pathway. Time-course analysis showed that mTORC1 activation and autophagy-related abnormalities preceded overt Aβ accumulation, while pharmacological mTOR activation with MHY1485 further aggravated autophagic impairment and increased Aβ42 levels. Crucially, targeted mTORC1 inhibition with EN6 ameliorated autophagy-related abnormalities and was associated with reduced BACE1 abundance and CTFβ generation, together with a diminished global Aβ burden. This microenvironmental stabilization attenuated neuroinflammation, realigned neural networks, and rescued both cognitive and emotional deficits.
    CONCLUSION: Chronic stress-induced mTORC1 hyperactivation is associated with autophagic impairment, contributing to macro-circuit desynchronization and accelerated amyloid accumulation. Targeting the mTORC1-autophagy axis represents a potential therapeutic approach to mitigate neural network breakdown and neuropathology in stress-related neurodegenerative conditions.
    Keywords:  Alzheimer's disease; autophagy; depression comorbidity; mTOR signaling; neural network
    DOI:  https://doi.org/10.1002/cns.71174
  26. PLoS One. 2026 ;21(9): e0359269
    AZP2006 in Parkinson's disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex.
    Noelle Callizot, Georgia Culley, Grace Flower, Laura Rouvière, Véronique De Conto, Alexandre Wojcinski, Catherine Botto, Cecilia Estrella, Alexandre Henriques, Philippe Verwaerde.
      The pathohistological hallmarks of Parkinson's disease are aggregated alpha-synuclein and other aggregation-prone proteins (Lewy bodies). Recent studies show mechanistic as well as genetic connections between lysosomal dysfunction and Parkinson's disease pathology. A direct link between lysosomal function and Parkinson's disease might be the degradation of alpha-synuclein within the lysosomal system. Progranulin is necessary for maintaining lysosomal function, facilitating the activity of several lysosomal enzymes. Progranulin's exit from the endoplasmic reticulum and its lysosomal availability depend on an interaction with Prosaposin. AZP2006 (INN: Ezeprogind) is a small lysosomotropic neuroprotective molecule currently in clinical development in Progressive Supranuclear Palsy patients. Its neuroprotective effects involve the Progranulin/Prosaposin complex. In this study, we investigated the neuroprotective effects of AZP2006 in several Parkinson's-like models (vitro and vivo). We showed that AZP2006 was able to counteract a mitochondrial injury as well as the toxicity of alpha-synuclein preformed fibril spreading. We proved that Progranulin was involved in AZP2006's neuroprotective action, restoring lysosomal homeostasis and ultimately supporting the health of dopaminergic neurons. In light of this evidence, strategies with the aim of improving Progranulin and Prosaposin levels and activity offer a promising therapeutic approach in the context of proteinopathies such as Parkinson's disease.
    DOI:  https://doi.org/10.1371/journal.pone.0359269
  27. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250276. [Epub ahead of print]381(1960):
    From aggregate structure to disease trajectory: the role of the proteostasis network.
    Jessica Tittelmeier, Carmen Nussbaum-Krammer.
      Neurodegenerative diseases are characterized by the accumulation of a small number of misfolded proteins, yet they differ markedly in cellular vulnerability and clinical outcome. We propose that this heterogeneity arises from the interaction between two largely orthogonal variables: the structural identities of protein aggregates and the identities of the cellular proteostasis networks (PNs) that engage them. Protein aggregates exist as structurally diverse assemblies with distinct intrinsic properties. At the same time, PNs vary between cell types, disease states and ageing in their composition, capacity and plasticity. As a result, the same aggregate can be efficiently cleared in one cellular context but persist, be remodelled, or give rise to self-propagating species in another. Likewise, the same PN can be protective or harmful, depending on the aggregate it encounters. Because neither aggregates nor PNs are static, their interaction evolves over time, leading to dynamic feedback between aggregate identity and PN state that shapes disease onset, progression and clinical symptoms. This view reframes neurodegenerative disease as a failure of compatibility between specific aggregate structures and the cellular protein quality control network that processes them rather than as a uniform collapse of proteostasis, and provides a framework for understanding selective vulnerability and disease trajectories. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  chaperones; neurodegenerative diseases; prion-like propagation; protein aggregation; protein disaggregation; protein quality control; proteostasis network; structural polymorphs
    DOI:  https://doi.org/10.1098/rstb.2025.0276
  28. EMBO Rep. 2026 Oct 02.
    Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.
    Hiroshi Hanafusa, Kota Ohashi, Hiromu Shojima, Yurika Honda, Naoki Hisamoto, Takeshi Kameyama, Muneaki Miyata, Kiyohito Mizutani, Yoshimi Takai, Kunihiro Matsumoto.
      Parkinson's disease (PD) and related synucleinopathies are marked by the accumulation and propagation of α-synuclein (α-syn) aggregates, a process primarily studied in neurons. Whether astrocytes actively contribute to α-syn processing and intercellular transfer remains unclear. Here, using a physiologically relevant neuron-astrocyte co-culture system that recapitulates tripartite synapse architecture, we show that astrocytes process α-syn and influence the morphological maturation of neuronal aggregates. Astrocytes internalize α-syn pre-formed fibrils (PFFs) and generate C-terminally truncated α-syn species via a Cathepsin D (CtsD)-dependent process. PFF-loaded astrocytes transfer α-syn-containing material to neurons and promote the formation and maturation of pS129-α-syn-positive Lewy neurite (LN)-like aggregates. Notably, α-syn PFF exposure induces lysosomal membrane damage, a senescence-like reactive state, and CtsD upregulation in astrocytes. Although PFF-containing lysosomes undergo autophagic engulfment, they persist within astrocytes, and a subset is detected beyond the astrocytic membrane boundary. Together, our findings support a model in which astrocytic lysosomal remodeling of internalized α-syn contributes to the morphological maturation and intercellular propagation of neuronal α-syn pathology in this co-culture system.
    DOI:  https://doi.org/10.1038/s44319-026-00927-w
  29. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250266. [Epub ahead of print]381(1960):
    Proteostasis and ageing dissidence.
    Neethu Babu, Katie Whalen, Brian Freeman.
      Proteostasis, the process governing the dynamic regulation of protein synthesis, folding and degradation, is critical for maintaining cell function and organismal health. Ageing disrupts this intricate system, leading to inactive, misfolded and/or aggregated proteins that contribute to age-associated pathologies. Here, we explore current findings on proteostasis and its deterioration during ageing with an attention to three major pathways: molecular chaperone (MC), ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway. Components in all three paths undergo age-dependent decline in both expression and function, with each impairment having select initial outcomes on the health of a proteome. For example, loss in the MC path may cause nascent chain defects, whereas a decline in the UPS may result in the accumulation of toxic aggregates. Notably, the interconnectedness of these pathways results in reciprocal reactions in all three. Understanding how each path connects to the others and how these connections are regulated offers promising strategies to restore proteome integrity and extend a healthy lifespan. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  ageing; autophagy–lysosome pathway; molecular chaperone; proteostasis; ubiquitin–proteasome system
    DOI:  https://doi.org/10.1098/rstb.2025.0266
  30. EMBO Rep. 2026 Sep 28.
    PTEN-L inhibits mitophagy and GSDME-dependent pyroptosis via Parkin dephosphorylation.
    Chenghao Yan, Cainian Huang, Xu Liu, Yifan Liu, Yancheng Tang, Zhixuan Zhu, Jiaqi Qi, Hao Guo, Ying Li, Yuyuan Zhu, Lijie Wang, Yufei Luo, Linlin Xing, Haiji Wang, Faxiang Li, Bo Sun, Sulai Liu, Guang Lu, Haodong Xu, Bo Zhou, Han-Ming Shen, Liming Wang.
      Mitochondrial dysfunction is a potent trigger of inflammatory cell death; however, the precise signaling pathways linking mitochondrial damage to pyroptosis remain incompletely understood. Here, we identify a previously unrecognized pathway in which mitochondrial depolarization activates the PINK1-Parkin axis to drive GSDME-mediated pyroptosis, a process negatively regulated by the phosphatase PTEN-L. Upon activation, Parkin promotes the ubiquitination and proteasomal degradation of MCL-1, facilitating mitochondrial translocation and activation of BAX. This triggers cytochrome c release, caspase-3 activation, and subsequent cleavage and plasma membrane targeting of GSDME, ultimately leading to pyroptotic cell death. Conversely, PTEN-L functions as a master negative regulator that counteracts Parkin through dephosphorylation and inactivation of Parkin. This action not only suppresses mitophagy but also stabilizes MCL-1, thereby inhibiting the downstream BAX/BAK-caspase-3-GSDME cascade and subsequent pyroptosis. Thus, our findings reveal a phosphorylation-dependent regulatory switch centered on Parkin that functionally couples mitophagy regulation to GSDME-dependent pyroptosis, delineating a novel mitochondrial signaling pathway that integrates organelle quality control with cellular fate decisions under stress conditions.
    DOI:  https://doi.org/10.1038/s44319-026-00957-4
  31. Bioorg Chem. 2026 Sep 30. pii: S0045-2068(26)01144-2. [Epub ahead of print]183 110608
    A lysosome-targeted dual-lock fluorescent probe based on synergistic pH/viscosity response for visualizing autophagy and tumor tissues.
    Yaqiong Kong, Rong Wu, Lehua Cheng, Lei Li, Zhong Xie, Duojun Cao, Mengdi Lv.
      The pH value and viscosity in the lysosomal microenvironment play a crucial role in maintaining cellular homeostasis, and their abnormalities are closely related to various diseases. However, most of the existing fluorescent probes only respond to a single parameter, such as pH or viscosity, making it difficult to achieve highly specific imaging. Therefore, in this study, a novel "dual-lock" activated fluorescent probe BT-CZ was designed and synthesized based on the "AND gate" logic. This probe only turns on green fluorescence when both acidic conditions and high viscosity are present, effectively avoiding false positive signals caused by single environmental fluctuations. In vitro experiments demonstrated that BT-CZ exhibits sensitivity to viscosity and high selectivity under acidic conditions. Cell imaging and orthogonal pharmacological experiments confirmed that it can accurately target lysosomes and exhibit "dual-lock" activation behavior. Using the EBSS starvation-induced autophagy model, BT-CZ successfully monitored the coordinated alterations in lysosomal acidity and viscosity and could distinguish between functional autophagy and autophagic flux blockage. Notably, BT-CZ demonstrated effectiveness in the real-time in-situ diagnosis of tumor tissues with almost no background signal in normal organs.
    Keywords:  Autophagy; Dual-lock fluorescent probe; Lysosomal; Tumor imaging; pH and viscosity
    DOI:  https://doi.org/10.1016/j.bioorg.2026.110608
  32. bioRxiv. 2026 Sep 27. pii: 2026.09.21.753276. [Epub ahead of print]
    DEPP1 connects nutrient and oxygen availability to maintenance of muscle mass.
    Shariq Qayyum, Christopher Lavallee, Madhu Singh, Gregory Wyant.
      Nutrients and oxygen are sensed within the muscle to control growth and disruption of either signal is sufficient to lead to muscle atrophy. While nutrient limitation is sensed via a conserved transcriptional atrophy program (commonly referred to as atrogenes) dictated via the Forkhead box O (FoxO) transcription factors, how low oxygen promotes muscle loss remains unknown. Accordingly, the downstream mechanisms that initiate muscle loss when oxygen and nutrients are limiting are only partly understood. Here, we find Hypoxia Inducible Factor (HIF), the master regulator of our adaptation to low oxygen, is necessary and sufficient to mediate muscle loss under hypoxia in mice. RNA sequencing in skeletal muscle isolated from starved or hypoxic mice identifies Decidual Protein Induced by Progesterone 1 (Depp1), which is induced in skeletal muscle when nutrients or oxygen is limiting via FoxO1 and HIF activation, respectively. Whole body Depp1 loss in mice reduces muscle loss under fasting and hypoxia and skeletal muscle Depp1 overexpression is sufficient to mediate muscle atrophy. Mechanistically, Depp1 localizes to the mitochondria and is necessary to control autophagy activation and mitochondrial degradation in skeletal muscle. Taken together, our studies nominate Depp1 as a new atrogene necessary for muscle loss under multiple atrophy scenarios involving FoxO and HIF.
    DOI:  https://doi.org/10.64898/2026.09.21.753276
  33. Metab Brain Dis. 2026 Sep 28. pii: 228. [Epub ahead of print]41(1):
    Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets.
    Sumeyye Yildirim.
      According to the Global Burden of Disease Study 2023, Parkinson's disease (PD) affects an estimated 11.67 million people worldwide, a progressive neurodegenerative condition marked by the accumulation of Lewy bodies containing α-synuclein and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Over the past ten years, advances in genetic and molecular research have shown that PD pathogenesis involves interrelated mechanisms such as impaired protein homeostasis, mitochondrial dysfunction, oxidative stress, defects in lysosomal-autophagic pathways, and chronic neuroinflammation, which go beyond dopaminergic neuronal loss. This review summarizes new data about major genes associated with monogenic and polygenic forms of PD, including SNCA, LRRK2, PRKN, PINK1, DJ-1 (PARK7), GBA1, VPS35, ATP13A2, FBXO7, and the GWAS-prioritized risk genes TMEM175, SCARB2, CTSB, RIT2, DYRK1A, and BAG3, together with the molecular pathways disrupted by these genetic alterations in light of current evidence. The polygenic architecture of PD and ancestry-related variation in genetic risk are also discussed. α-synuclein aggregation and proteostasis networks, oxidative stress, autophagy and mitophagy failure, neuroinflammation, mitochondrial quality control, and epigenetic regulation are all given special attention. Apart from traditional dopaminergic treatments, new therapeutic approaches such as immunotherapies targeting α-synuclein, gene therapies mediated by adeno-associated virus (AAV), induced pluripotent stem cell (iPSC)-based methods, and genotype-guided precision medicine are critically examined. A more comprehensive understanding of the molecular mechanisms underlying PD is expected to facilitate the development of reliable biomarkers and accelerate the clinical translation of disease-modifying therapies.
    Keywords:  Autophagy; Genetic architecture; LRRK2; Mitochondrial dysfunction; Molecular pathogenesis; Neuroinflammation; Neuroprotection; Parkinson''s disease; α-synuclein
    DOI:  https://doi.org/10.1007/s11011-026-01998-3
  34. MedComm (2020). 2026 Oct;7(10): e70949
    Posttranslational Modifications of p62/SQSTM1 in Health and Disease.
    Weikai Wang, Xin Jiang, Runing Qiu, Chandra Sugiarto Wijaya, Miaoqin Chen, Jin Wang, Liyuan Zhu, Hongchuan Jin, Lifeng Feng.
      p62/SQSTM1 is a multifunctional adaptor protein that serves as a central hub integrating cellular stress responses, including selective autophagy, antioxidant defense, metabolism, and immune signaling. Its diverse functions are precisely orchestrated by a complex network of posttranslational modifications (PTMs) that dynamically regulate its conformation, protein interactions, stability, and subcellular localization. This review provides a comprehensive overview of the p62 PTMs landscape, encompassing phosphorylation, ubiquitination, acetylation, methylation, and emerging cysteine-based modifications. We first discuss how these PTMs coordinately maintain cellular homeostasis by fine-tuning autophagic flux, activating antioxidant programs, coordinating nutrient sensing, preserving genomic stability, and regulating immune responses. We then examine how dysregulation of this PTMs network drives pathogenesis in major diseases including cancer, neurodegenerative disorders, metabolic diseases, and infections, with emphasis on context-dependent molecular mechanisms. Furthermore, we summarize current preclinical evidence targeting p62 PTMs. Finally, we emphasize the critical need for advanced technologies to decipher PTMs crosstalk and dynamic regulation, coupled with the development of corresponding therapeutic strategies, to advance precision medicine. Understanding the p62 PTMs code offers promising opportunities for developing novel biomarkers and targeted therapies for human diseases.
    Keywords:  autophagy; disease; homeostasis; p62/SQSTM1; posttranslational modifications; signal transduction; therapeutic target
    DOI:  https://doi.org/10.1002/mco2.70949
  35. Toxicon. 2026 Oct 01. pii: S0041-0101(26)00332-6. [Epub ahead of print] 109314
    p38 MAPK-associated autophagic response restrains TLR4/MyD88 signaling in RT-treated macrophages.
    Suli Song, Mingxin Dong, Chengbiao Sun, Na Zhao, Mingyang Huo, Changshun Lv, Yan Wang, Na Xu, Ye Xu, Wensen Liu.
      Ricin toxin (RT) is a highly potent plant-derived toxin that causes severe cellular injury and inflammatory responses, yet effective therapeutic interventions remain limited. Autophagy is a conserved stress-response pathway that maintains intracellular homeostasis and modulates innate immune signaling. However, whether autophagy contributes to macrophage adaptation during RT intoxication and how this process is regulated remain incompletely understood. In this study, we investigated RT-induced autophagic responses and their relationship with TLR4/MyD88 signaling in RAW264.7 macrophages using transmission electron microscopy, immunofluorescence staining, tandem mRFP-eGFP-LC3 reporter analysis, Western blotting, and Atg5 knockdown/overexpression approaches. RT treatment induced autophagic vacuole formation, increased LC3 puncta, and elevated the expression of LC3-II, Atg5, Beclin-1, and p62, with LC3 puncta peaking at 2 h after stimulation. Tandem LC3 reporter analysis further supported activation of autophagic flux during the early response to RT. Pharmacological inhibition of autophagy with 3-methyladenine reduced LC3-II accumulation and aggravated RT-associated loss of cell viability, suggesting a cytoprotective role of autophagy. Mechanistically, RT increased p38 MAPK phosphorylation, and inhibition of p38 MAPK activity with SB203580 attenuated RT-induced LC3 puncta formation, whereas JNK inhibition showed no obvious effect under the same conditions. Furthermore, Atg5 knockdown enhanced RT-induced TLR4 and MyD88 protein expression and IL-1β secretion, whereas Atg5 overexpression suppressed these responses; TRIF expression was not markedly altered. These findings suggest that RT triggers an early p38 MAPK-associated autophagic response in macrophages and that Atg5-dependent autophagy restrains TLR4/MyD88-associated innate immune signaling. This study provides mechanistic insight into the adaptive cellular response to RT exposure and identifies autophagy as a potential modulatory pathway in RT-induced macrophage injury.
    Keywords:  Atg5; Ricin toxin; TLR4/MyD88 signaling; autophagy; p38 MAPK
    DOI:  https://doi.org/10.1016/j.toxicon.2026.109314
  36. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250270. [Epub ahead of print]381(1960):
    More than the 'master regulator of cytosolic proteostasis': new roles for HSF1 in promoting tissue health.
    John Labbadia.
      Maintaining protein homeostasis (proteostasis) is crucial for long-term tissue health. This requires the action of stress response pathways and protein quality control mechanisms that act within or across different sub-cellular compartments to preserve proteome integrity. Within the cytosol/nucleus, the loss of proteostasis induces a transcriptional programme known as the heat-shock response (HSR) through activation of heat-shock factor 1 (HSF1). The HSR rapidly elevates levels of molecular chaperones, co-chaperones and protein degradation factors that restore proteostasis in the cytosol/nucleus. As a result, the ability of HSF1 to promote tissue health has long been attributed to its capacity to safeguard the cytosolic/nucleosolic proteome. However, over the past 15 years, it has become apparent that HSF1 activity is also intimately coupled with the biogenesis and maintenance of other organelles, including mitochondria, peroxisomes, the endoplasmic reticulum, lysosomes and chloroplasts. This suggests that HSF1 promotes tissue health in plants and animals through mechanisms beyond the maintenance of cytosolic/nucleosolic proteostasis. In this opinion piece, I will discuss advances in our understanding of the interplay between HSF1 and organelle homeostasis and make the case that the existing model for the relationship between HSF1 and tissue health should be expanded to encompass these additional roles. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  HSF1; healthy ageing; organelle homeostasis; proteostasis; stress responses
    DOI:  https://doi.org/10.1098/rstb.2025.0270
  37. Aging Cell. 2026 Oct;25(10): e70726
    Dietary CoQ10 Ameliorates Age-Related Megakaryocyte Dysfunction via COPS3-Mediated Activation of Autophagy.
    Yixuan Xu, Yu-Heng Mao, Fenglin Song, Fang He, Yueying Wu, CaiXia Wang, Minghan Wang, Shuangfeng Xie, Heyu Ni, Yan Yang.
      Age-related megakaryocyte (MK) dysfunction disrupts platelet production and may increase thrombotic risk, but whether coenzyme Q10 (CoQ10) restores MK homeostasis through autophagy remains unclear. Male C57BL/6J mice aged 1, 9, 15, 19, 21, or 23 months received CoQ10 for 12 weeks. Bone marrow MK proliferation, CD41/CD61 expression, DNA polyploidy, autophagy-associated proteins, and platelet phenotypes were evaluated. H2O2-induced senescent MEG-01 cells were used for pharmacological modulation with rapamycin and LY294002, bafilomycin A1-based autophagic flux assays, and COPS3 knockdown. CoQ10 enhanced MK proliferation, maturation, and polyploidization in aged mice. Changes in the LC3-II/LC3-I ratio and p62 in bone marrow MKs were consistent with enhanced autophagy. Proteomic analysis identified increased COPS3 abundance in MKs from CoQ10-treated 24-month-old mice. In senescent MEG-01 cells, responses to rapamycin and LY294002 supported the involvement of autophagy-related signaling in the effects of CoQ10. CoQ10 increased COPS3 expression even under autophagy-inhibitory conditions and produced greater bafilomycin A1-sensitive LC3-II accumulation, supporting increased autophagic flux. COPS3 knockdown attenuated CoQ10-induced changes in autophagy-associated markers and partially diminished its effects on MK maturation and polyploidization, indicating that COPS3 contributes to, but may not solely mediate, these responses. CoQ10 did not alter platelet counts in naturally aged mice but was associated with reduced platelet aggregation and activation. Together, these findings suggest that CoQ10 ameliorates age-related MK dysfunction and platelet hyperreactivity, in part through COPS3-associated autophagy regulation. These findings provide a mechanistic basis for further investigation of CoQ10 as a nutritional strategy for age-related platelet dysfunction.
    Keywords:  COPS3; CoQ10; aging; autophagy; megakaryocyte
    DOI:  https://doi.org/10.1111/acel.70726
  38. Adv Sci (Weinh). 2026 Sep 27. e78018
    Huntingtin Aggregate-Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice.
    Jie Zhu, Xi-Xiu Xie, Lei Li, Chen Tian, Hao-Tian Wang, Xiao-Jie Wang, Xiao-Lin Yu, Gui-Feng Zhang, Rui-Tian Liu.
      The accumulation of mutant huntingtin (mHTT) aggregates drives the pathology of Huntington's disease (HD), yet therapies capable of distinguishing toxic species from wild-type proteins remain elusive. Here, a synthetic gene circuit, termed ARAA, was engineered to couple the preferential recognition of aggregated polyQ species to the on-demand activation of autophagy. Utilizing a repurposed bacterial NarX-NarL system fused with a conformation-sensitive intrabody, the circuit detects pathological polyQ conformers and triggers the transcriptional expression of the master autophagy regulator TFEB. To enable systemic application, the ARAA plasmid is encapsulated in CD98-targeted immunoliposomes (LIP-CD98) that facilitate efficient blood-brain barrier crossing via receptor-mediated transcytosis. In the R6/2 HD mouse model, ARAA treatment significantly reduces mHTT burden, attenuates neuroinflammation, and rescues synaptic deficits. This closed-loop intervention improves motor function and extends lifespan. Together, these findings provide proof-of-concept evidence that aggregate-responsive regulation of autophagy can mitigate disease-associated phenotypes in exon 1-based HD models.
    Keywords:  Huntington's disease; TFEB; autophagy; immunoliposome; neuroprotection; polyglutamine; synthetic gene circuit
    DOI:  https://doi.org/10.1002/advs.78018
  39. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2612904123
    TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation.
    Tomohide Kinoshita, Akira Nakajima, Toru Kobayashi, Mai Ohno, Yuxi Wei, Tatsumasa Hasegawa, Norihito Hayatsu, Shoshiro Hirayama, Yu-Ichi Tsukada, Atsushi Hirao, Shigeo Murata, Shohei Hori.
      Regulatory T (Treg) cell differentiation and function rely on stable expression of the master transcription factor Foxp3. While Foxp3 expression is epigenetically stabilized through DNA demethylation of a Foxp3 enhancer (the Treg-specific demethylated region, TSDR), the mechanisms underlying this process remain unclear. Here, we show that strong and sustained T cell receptor (TCR) signaling promotes TSDR demethylation, stabilizes Foxp3 expression, and confers suppressive activity in in vitro-induced Treg (iTreg) cells through activation of mTORC1. Mechanistically, TCR-mTORC1 signaling promotes TSDR demethylation by enhancing translation of TET2, and likely TET3, enzymes that mediate DNA demethylation. Rescue of impaired TSDR demethylation under mTORC1 inhibition by the TET2 catalytic domain, together with dose-dependent impairment following heterozygous deficiency of TET2 and/or TET3, supports a causal link between TET protein abundance and TSDR demethylation. In vivo, mTORC1 inactivation increases the frequency of cells harboring a methylated TSDR among peripheral Foxp3+ T cells, but not among developing Foxp3+ thymocytes, supporting in vivo relevance of mTORC1-dependent epigenetic remodeling. Thus, TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression through translational control of TET proteins, revealing an unrecognized role for mTORC1 in iTreg cell differentiation.
    Keywords:  DNA demethylation; Foxp3; T cell receptor; mTORC1; regulatory T cells
    DOI:  https://doi.org/10.1073/pnas.2612904123
  40. Assay Drug Dev Technol. 2026 Sep 30. 1540658X261490394
    Yeast-Based High-Throughput Screening Platform for Identifying Modulators of Mitochondrial Protein Import.
    Maya Cielo Cornejo, Sandy Che-Eun S Lee, Christina Nguyen, Shaya Smith, Cameron Taylor, Robert Damoiseux, Carla M Koehler.
       Mitochondrial protein import is essential for overall cellular homeostasis, yet scalable approaches to systematically interrogate mitochondrial protein import and identify modulators of this process remain limited. Here, we describe a yeast-based, gain-of-growth (GoG), high-throughput screening assay for the identification of small-molecule modulators of mitochondrial protein import. In this system, truncated human proteins that contain N-terminal mitochondrial targeting sequences (MTSs) are expressed in S. cerevisiae, where mitochondrial protein import is coupled to an auxotrophic growth readout. Disruption of import leads to cytosolic accessibility of the URA3 reporter, producing a GoG phenotype under selective conditions. As a proof of concept, we applied this model to PTEN-induced kinase 1 (PINK1), a mitochondrial imported regulator of mitochondrial quality control. Using this approach, we demonstrate the ability to monitor PINK1 import and identify candidate compounds that modulate this process. Collectively, this work establishes a scalable and reproducible platform for interrogating mitochondrial protein import and identifying compounds for downstream validation in mammalian systems.
    Keywords:  N-terminal targeting sequence; PINK1; high-throughput screening; mitochondrial protein import
    DOI:  https://doi.org/10.1177/1540658X261490394
  41. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250275. [Epub ahead of print]381(1960):
    Cellular and systemic modifiers of alpha-synuclein proteostasis.
    Suzanne Couzijn, Anna P Ainslie, Alejandro Herron-Bedoya, Ellen A A Nollen.
      Ageing is a primary risk factor for neurodegenerative disorders, including Parkinson's disease (PD). As individuals age, their cells become less efficient in maintaining protein homeostasis, leading to an increased likelihood of protein misfolding and aggregation. A hallmark of PD and other synucleinopathies is the accumulation of alpha-synuclein protein aggregates in affected neurons, a process that is exacerbated by ageing. While cellular mechanisms that regulate protein aggregation have been a primary focus of research, recent studies suggest that other, systemic age-related mechanisms may contribute to alpha-synuclein toxicity. Understanding these alternative pathways is crucial for the development of effective therapeutic strategies to combat neurodegenerative diseases, such as PD. In this review, we synthesize current insights into the biological mechanisms underlying alpha-synuclein toxicity at the organismal level. We highlight key open questions and discuss how these findings may inform the development of targeted interventions to prevent or delay age-related synucleinopathies. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  ageing; alpha-synuclein; protein aggregation; protein condensation; proteostasis
    DOI:  https://doi.org/10.1098/rstb.2025.0275
  42. Dev Cell. 2026 Oct 02. pii: S1534-5807(26)00349-7. [Epub ahead of print]
    Nitrate-responsive Sialin2 couples stress granule assembly and clearance to maintain neuronal homeostasis.
    Xiaoyu Li, Zichen Cao, Ou Jiang, Songyue Wu, Bo Zhou, Yao Feng, Xinyue Chen, Jinsong Wang, Jian Zhou, Renhong Yan, Mo Chen, Songlin Wang.
      Stress granules (SGs) are phase-separated ribonucleoprotein condensates that support cellular adaptation to acute stress, but how extracellular signals coordinate their assembly and recovery-phase clearance remains unclear. Here, we show that nitrate-responsive Sialin2 coordinates SG homeostasis across the stress cycle. During acute stress, Sialin2 undergoes liquid-liquid phase separation and co-assembles with Ras GTPase-activating protein SH3-domain-binding protein (G3BP)-centered scaffolds to promote SG formation. During recovery, Sialin2 preserves liquid-like SG dynamics and promotes autophagy-linked clearance. Sialin2 loss delays SG resolution, promotes retention of amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) variants, and enhances amyloid precursor protein (APP)-related amyloidogenic output. In an ALS mouse model, nitrate treatment reduces SG-like pathology and neuroinflammation, preserves neuronal integrity, and delays functional decline. Together, these findings define a nitrate-Sialin2 signaling module that couples SG assembly to recovery-phase clearance and links inorganic anion sensing to protection against neurodegeneration.
    Keywords:  Sialin2; autophagy; liquid-liquid phase separation; neurodegeneration; nitrate; stress granules
    DOI:  https://doi.org/10.1016/j.devcel.2026.09.001
  43. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250273. [Epub ahead of print]381(1960):
    Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.
    James F Morley.
      Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  co-pathology; neurodegeneration; proteostasis
    DOI:  https://doi.org/10.1098/rstb.2025.0273
  44. Mol Genet Metab. 2026 Sep 24. pii: S1096-7192(26)00548-2. [Epub ahead of print]149(3): 110265
    CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.
    Hamid Esmaeili, Supta Das, Krystyna Rytel, Ellen Sidransky, Yu Chen.
      Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.
    Keywords:  CRISPR screens; Gaucher disease; Genetic modifiers; Lysosomal storage disorders; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110265
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