bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2026–01–11
28 papers selected by
TJ Krzystek
  1. Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.
  2. TBK1 orchestrates autophagy and endo-lysosomal pathways in human neurons.
  3. Mitochondria and the Actin Cytoskeleton in Neurodegeneration.
  4. TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia.
  5. Multilevel Screening Platform Utilizing Cellular and Zebrafish Models to Identify Short Peptides with High Improvement of Motor Neuron Growth.
  6. Autophagy-Lysosome Pathway Dysfunction in Neurodegeneration and Cancer: Mechanisms and Therapeutic Opportunities.
  7. Calcium overload induced mitochondrial and lysosomal dysfunction is regulated by Tousled-like kinase in a-synucleinopathy.
  8. Proteasomal Degradation of Mutant Huntingtin Exon1 Regulates Autophagy.
  9. Quantitative optical nanoscopy of mitochondrial-derived vesicles in neurons classifies pre-peroxisomal and clearing organelles.
  10. A Rab1 interactome illuminates a dual role in autophagy and membrane trafficking.
  11. A Syd and RUFY dynein adaptor complex mediates axonal circulation of dense core vesicles.
  12. A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis.
  13. The ATG8 E3-like ligases sense lysosomal damage and initiate ESCRT-mediated membrane repair.
  14. Plasma membrane-to-lysosome FGR signaling regulates endocytosis-associated lysosome homeostasis.
  15. Treatment of Huntington's disease with a pan-HTT-targeting CRISPR nuclease.
  16. Mitophagy in the pathogenesis and management of disease.
  17. Mitochondrial dynamics and signaling in stem cell differentiation.
  18. Genetic Modeling of Lysosomal Storage Disorders (LSDs) in the Brain-Midgut Axis of Drosophila melanogaster During Aging.
  19. Transcriptional code for circuit integration in the injured brain by transplanted human neurons.
  20. Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.
  21. Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice.
  22. Aβ plaques induce local pre-synaptic toxicity in human iPSC-derived neuron xenografts.
  23. Membrane-protein-mediated phase separation orchestrates organelle contact sites.
  24. Mutations in the Rab33b protein that lead to the skeletal disease Smith-McCort dysplasia result in unstable proteins and altered autophagy function.
  25. Generation of two human iPSC lines from fibroblasts of BPAN patients carrying pathogenic variants in the WDR45 gene.
  26. Primary cortical neurons precipitate and extrude large mitochondria-associated calcium-phosphate sheets with a bone-precursor-like ultrastructure.
  27. AMT-130 gene therapy: a promising disease-modifying approach for Huntington's disease.
  28. Measuring lysosome damage and lysophagy in vivo.
  1. J Cell Biol. 2026 Feb 02. pii: e202212064. [Epub ahead of print]225(2):
    Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.
    Aaron Byrd, Lucas J Marmorale, Sophia Marcinowski, Megan M Dykstra, Vanessa Addison, Sami J Barmada, J Ross Buchan.
      A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation, stability, and toxicity. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation induces giant MVB-like vesicles, within which TDP-43 accumulates in a NEDD4-dependent manner. Our studies shed light on endolysosomal-mediated cytoplasmic protein clearance, a poorly understood proteostasis mechanism, which may help identify novel ALS therapeutic strategies.
    DOI:  https://doi.org/10.1083/jcb.202212064
  2. Autophagy. 2026 Jan 04. 1-3
    TBK1 orchestrates autophagy and endo-lysosomal pathways in human neurons.
    Daniel A Mordes, Julie Smeyers.
      Haploinsufficiency of TBK1 causes familial ALS and frontotemporal dementia (FTD), yet the mechanisms by which TBK1 loss leads to neurodegeneration remain unclear. Using deep proteomics and phospho-proteomics, we demonstrate that TBK1 regulates select macroautophagy/autophagy factors, targeting cargo receptors and autophagy initiation factors, and also sustains the phosphorylation of the late endosomal marker RAB7A in stem cells and stem cell-derived excitatory neurons. We further uncovered novel TBK1-dependent phosphorylation sites in the key autophagy protein SQSTM1/p62. Loss of TBK1 function results in a cell-autonomous neurodegenerative phenotype characterized by impaired neurite outgrowth and lysosomal dysfunction.
    Keywords:  TBK1; lysosomes; neurodegeneration; proteomics; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2609924
  3. Cytoskeleton (Hoboken). 2026 Jan 08.
    Mitochondria and the Actin Cytoskeleton in Neurodegeneration.
    Shivani Tuli, Preet Patel, Aneri Shethji, David Gau.
      Mitochondrial dysfunction and cytoskeletal disorganization are widely recognized hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although these disorders differ in clinical presentation and etiology, accumulating evidence points to a shared cellular vulnerability at the intersection of mitochondrial dynamics and actin cytoskeletal regulation. In this review, we examine the emerging role of actin-mitochondria crosstalk as a convergent mechanism in neurodegeneration. We discuss how disruptions in actin filament remodeling, mitochondrial fission and fusion, organelle transport, and mitophagy contribute to neuronal dysfunction and loss across these diseases. Particular attention is given to disease-specific pathways, including cofilin-actin rod formation in AD, α-synuclein-driven actin disruption in PD, mutant huntingtin's effects on mitochondrial fragmentation in HD, and profilin-1-associated mitochondrial defects in ALS. By synthesizing findings from diverse models, we highlight how perturbations in the cytoskeleton-mitochondria interface may act as an upstream trigger and amplifier of neurodegenerative cascades. We also outline key knowledge gaps and propose future directions for research, with an emphasis on targeting actin-mitochondrial interactions as a potential therapeutic strategy across multiple neurodegenerative conditions.
    Keywords:  actin cytoskeleton; mitochondria dysfunction; mitochondria‐cytoskeleton crosstalk; neurodegeneration
    DOI:  https://doi.org/10.1002/cm.70095
  4. PLoS Biol. 2026 Jan;24(1): e3003573
    TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia.
    Vidhya Maheswari Jawahar, Yi Zeng, Ellen M Armour, Mei Yue, Kathryn Citrano, Anastasiia Lovchykova, Madison M Reeves, Bailey Rawlinson, Michael DeTure, Judith A Dunmore, Yuping Song, Sophie K Ball, Zbigniew K Wszolek, Neill R Graff-Radford, Bradley F Boeve, David S Knopman, Gregory S Day, Scott A Small, Dennis W Dickson, Michael E Ward, Tania F Gendron, Yongjie Zhang, Mercedes Prudencio, Aaron D Gitler, Leonard Petrucelli.
      TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region lengthening events in the brains of individuals with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), focusing on the functional impact of APA dysregulation. To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex. We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset. Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA. Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits.
    DOI:  https://doi.org/10.1371/journal.pbio.3003573
  5. Int J Mol Sci. 2025 Dec 26. pii: 281. [Epub ahead of print]27(1):
    Multilevel Screening Platform Utilizing Cellular and Zebrafish Models to Identify Short Peptides with High Improvement of Motor Neuron Growth.
    Bing-Chang Lee, Chun-Cheng Wang, Shan-Pin Chen, Huai-Jen Tsai.
      Zebrafish is emerging as a model animal for phenotype-based drug screening. Drugs screened from the zebrafish platform have advanced into clinical trials, underscoring their translational potential. Amyotrophic lateral sclerosis is a progressive motor neurons (MN) degenerative disease with few approved drugs. Previously, supplementation with exogenous recombinant phosphoglycerate kinase 1 (Pgk1) was found to improve MN growth through its interaction with receptor Eno2. To bypass the high complexity and cost of full-length Pgk1 production, a short segment within Pgk1 (M08) was predicted as the key motif interacting with Eno2, and a zebrafish phenotypic screening platform was established to find the most neurotrophic compound(s) among M08 and its mutants. We first found that M08-injected zebrafish embryos significantly increased branched caudal primary MNs (CaPMNs). However, compared to M08 (59.20 ± 1.80%), M039, among 17 mutants further screened, showed even more improvement of branched CaPMNs, up to 74.54 ± 3.73%. Next, when we administered the M039 peptide to C9ORF72-knockdown ALS-like zebrafish embryos, it improved axonal growth and swimming ability. Then, we employed a cellular model as a secondary screen, and M039 exhibited improved neurite outgrowth of MN (NOMN) and reduced p-Cofilin in NSC34 neural cells grown in ALS-like condition. Therefore, by using a zebrafish MN phenotype as a primary screening platform, we identified a mutated short peptide M039 having the most pronounced positive effect on improving neurite growth among all 17 mutants in comparison to parental M08, demonstrating the feasibility of zebrafish screening as a cost-effective strategy for finding promising neuroprotective short peptides that serve as neurotherapeutic potentials.
    Keywords:  motor neurons; neuroprotection; phenotypes; short peptides; zebrafish
    DOI:  https://doi.org/10.3390/ijms27010281
  6. Int J Mol Sci. 2025 Dec 29. pii: 366. [Epub ahead of print]27(1):
    Autophagy-Lysosome Pathway Dysfunction in Neurodegeneration and Cancer: Mechanisms and Therapeutic Opportunities.
    Mingyang Du, Yang Yu, Jiachang Wang, Cuicui Ji.
      The autophagy-lysosome system is a master regulator of cellular homeostasis, integrating quality control, metabolism, and cell fate through the selective degradation of cytoplasmic components. Disruption of either autophagic flux or lysosomal function compromises this degradative pathway and leads to diverse pathological conditions. Emerging evidence identifies the autophagy-lysosome network as a central signaling hub that connects metabolic balance to disease progression, particularly in neurodegenerative disorders and cancer. Although cancer and neurodegenerative diseases exhibit seemingly opposite outcomes-uncontrolled proliferation versus progressive neuronal loss-both share common mechanistic foundations within the autophagy-lysosome axis. Here, we synthesize recent advances on the roles of autophagy and lysosomal mechanisms in neurodegenerative diseases and cancer, especially on how defects in lysosomal acidification, membrane integrity, and autophagosome-lysosome fusion contribute to toxic protein accumulation and organelle damage in Alzheimer's and Parkinson's diseases, while the same machinery is repurposed by tumor cells to sustain anabolic growth, stress tolerance, and therapy resistance. We also highlight emerging lysosome-centered therapeutic approaches, including small molecules that induce lysosomal membrane permeabilization, nanomedicine-based pH correction, and next-generation protein degradation technologies. Finally, we discuss the major challenges and future opportunities for translating these mechanistic insights into clinical interventions.
    Keywords:  autophagy; cancer; lysosome; neurodegenerative disease
    DOI:  https://doi.org/10.3390/ijms27010366
  7. Cell Death Dis. 2026 Jan 08. 17(1): 10
    Calcium overload induced mitochondrial and lysosomal dysfunction is regulated by Tousled-like kinase in a-synucleinopathy.
    Fangyan Gong, Qi Cheng.
      As a pathological hallmark of Parkinson's disease (PD), a-synucleinopathy induces various cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, ultimately resulting in dopaminergic neuron death. However, the hierarchy of these detrimental events remains unclear. It is well established that a-synuclein can induce calcium overload through diverse mechanisms. To assess whether calcium overload plays a crucial detrimental role, we established a calcium overload model in Drosophila and conducted genetic screening. Our findings indicate that calcium overload caused mitochondrial damage and lysosomal dysfunction, leading to cell death, and these cytotoxic processes were significantly mitigated by the loss of Tousled-like kinase (TLK). Notably, the loss of TLK also ameliorated defects induced by a-synuclein overexpression in Drosophila. This suggests that calcium overload is a critical event in a-synucleinopathy. In mammalian cells and mice, calcium overload activated TLK2 (the homologue of Drosophila TLK) by enhancing TLK2 phosphorylation, which increases TLK2 kinase activity. Increased TLK2 phosphorylation was detected in the brains of GluR1Lc and a-synuclein overexpression mice, suggesting that TLK2 is activated under these pathological conditions. Furthermore, TLK2 knockout mice exhibited rescue of multi-aspect cytotoxicity induced by calcium overload and a-synuclein overexpression. Our research demonstrates that TLK2 activation by calcium overload appears to be a pivotal step in the progression of PD. This finding provides a potential link between calcium overload, the subsequent mitochondrial and lysosomal dysfunction observed in the disease.
    DOI:  https://doi.org/10.1038/s41419-025-08213-8
  8. Cells. 2025 Dec 30. pii: 68. [Epub ahead of print]15(1):
    Proteasomal Degradation of Mutant Huntingtin Exon1 Regulates Autophagy.
    Austin Folger, Chuan Chen, Phasin Gonzalez, Sophia L Owutey, Yanchang Wang.
      Accumulation of misfolded proteins is implicated in neurodegenerative diseases. One of these is Huntington's disease, which is caused by an expansion of trinucleotide (CAG) repeats in exon 1 of huntingtin gene (HTT). This expansion results in the production of mutant huntingtin exon1 protein (mHttEx1) containing polyglutamine tracks that is prone to cytotoxic aggregation. These mHttEx1 aggregates range from small soluble aggregates to large insoluble inclusion bodies. The mechanisms to clear mHttEx1 aggregates include ubiquitin-dependent proteasomal degradation and autophagy. For the proteasomal degradation of mHttEx1, ubiquitinated protein is first recognized by the Cdc48 complex for extraction and unfolding. For autophagy, mHttEx1 inclusion bodies are engulfed by an autophagosome, which fuses with the vacuole/lysosome and delivers cargo for vacuolar degradation. We name this autophagy IBophagy. In this study, we further show that the ubiquitination of mHttEx1 by the E3 ligase San1, its extraction and unfolding by the Cdc48 complex, and subsequent proteasomal degradation are all essential steps for mHttEx1 IBophagy in budding yeast, revealing a new layer of autophagy regulation and mHttEx1 cytotoxicity.
    Keywords:  Cdc48 complex; IBophagy; autophagy; misfolded proteins; mutant huntingtin exon1 (mHttEx1); proteasome
    DOI:  https://doi.org/10.3390/cells15010068
  9. Nat Commun. 2026 Jan 08.
    Quantitative optical nanoscopy of mitochondrial-derived vesicles in neurons classifies pre-peroxisomal and clearing organelles.
    Giovanna Coceano, Jonatan Alvelid, Martina Damenti, Gabriella Ferretti, Johannes Mueller, Joanna Rorbach, Ilaria Testa.
      Healthy mitochondria are crucial for maintaining neuronal homeostasis. Their activity depends on a dynamic lipid and protein exchange through fusion, fission, and vesicular trafficking. Studying vesicles in neurons is challenging with conventional microscopy due to their small size, heterogeneity, and dynamics. We use multicolour stimulated emission depletion nanoscopy to uncover the ultrastructure of mitochondrial-derived vesicles (MDVs) in live neurons, biosensors to define their functional state, and a pulse-chase strategy to identify their turnover in situ. We identified three populations of vesicular structures: one transporting degradation products originating from oxidative stress, one shuttling cargo and newly translated proteins for local organelle biogenesis and one consisting of small, functional mitochondria. Furthermore, we provide evidence supporting that de novo peroxisomes biogenesis occurs via the fusion of endoplasmic reticulum and MDVs at mitochondrial sites. Our data provide mechanistic insight into organelle biogenesis driven by significant diversity in MDV morphology, functional state, and molecular composition.
    DOI:  https://doi.org/10.1038/s41467-025-68160-y
  10. J Cell Biol. 2026 Mar 02. pii: e202507084. [Epub ahead of print]225(3):
    A Rab1 interactome illuminates a dual role in autophagy and membrane trafficking.
    Alexander R van Vliet, Alison K Gillingham, Tomos E Morgan, Yohei Ohashi, Tom S Smith, Ferdos Abid Ali, Sean Munro.
      The small GTPase Rab1 is found in all eukaryotes and acts in both ER-to-Golgi transport and autophagy. Several Rab1 effectors and regulators have been identified, but the mechanisms by which Rab1 orchestrates these distinct processes remain incompletely understood. We apply MitoID, a proximity biotinylation approach, to expand the interactome of human Rab1A and Rab1B. We identify new interactors among known membrane traffic and autophagy machinery, as well as previously uncharacterized proteins. One striking set of interactors are the cargo receptors for selective autophagy, indicating a broader role for Rab1 in autophagy than previously supposed. Two cargo receptor interactions are validated in vitro, with the Rab1-binding site in optineurin being required for mitophagy in vivo. We also find an interaction between Rab1 and the dynein adaptor FHIP2A that can only be detected in the presence of membranes. This explains the recruitment of dynein to the ER-Golgi intermediate compartment and demonstrates that conventional methods can miss a subset of effectors of small GTPases.
    DOI:  https://doi.org/10.1083/jcb.202507084
  11. J Cell Biol. 2026 Mar 02. pii: e202507071. [Epub ahead of print]225(3):
    A Syd and RUFY dynein adaptor complex mediates axonal circulation of dense core vesicles.
    Viktor Karlovich Lund, Antony Chirco, Michela Caliari, Andreas Haahr Larsen, Kristoffer Tollestrup Tang, Ulrik Gether, Kenneth Lindegaard Madsen, Michael Wierer, Ole Kjaerulff.
      Neuropeptide-containing dense core vesicles (DCVs) generated in neuronal somata are circulated in axons to supply distal release sites, depending on kinesin-1, kinesin-3, and dynein, but how the motors are recruited remains unclear. Here we use proximity proteomics in the living Drosophila nervous system to identify the protein complex responsible for recruitment of kinesin-1 and dynein on DCVs. We find that the dynein and kinesin-1 adaptor Sunday driver (Syd/dJIP3/4) interact with the DCV-located GTPase Rab2 and also bind the Arl8 effector RUFY. Disrupting Rab2, Syd, RUFY, the Arl8 activator BORC, or dynein impedes retrograde DCV flux and induces axonal accumulation of immobile DCVs. Our data suggest that dynein is recruited and activated by a Syd/RUFY complex anchored to DCVs by Rab2 and Arl8. Rab2 loss but not disruption of Syd, RUFY, or dynein causes missorting of DCV membrane proteins into vesicle aggregates in motor neuron somata, suggesting that Rab2 employs separate effectors in DCV biogenesis and motility.
    DOI:  https://doi.org/10.1083/jcb.202507071
  12. Cells. 2025 Dec 24. pii: 37. [Epub ahead of print]15(1):
    A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis.
    Seyyed Bahram Borgheai, Brie E Achorn, Alyssa H Zisk, Sarah M Hosni, Karl E G Richter, Frank S Menniti, Yalda Shahriari.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS.
    Keywords:  amyotrophic lateral sclerosis; biomarkers; cognition; neurophysiology
    DOI:  https://doi.org/10.3390/cells15010037
  13. EMBO J. 2026 Jan 03.
    The ATG8 E3-like ligases sense lysosomal damage and initiate ESCRT-mediated membrane repair.
    Dale P Corkery, Deerada Wijayatunga, Benedita K L Feron, Laura K Herzog, Anastasia Knyazeva, Yao-Wen Wu.
      After damage from pathogenic, chemical or physical stress, endolysosomal membranes are repaired and resealed by the endosomal sorting complex required for transport (ESCRT) machinery, but how this membrane damage is sensed and translated into ESCRT recruitment is poorly understood. Here, we identify the two ATG8 E3-like ligases, ATG16L1 and TECPR1, as ion-dependent catalysts for ESCRT recruitment to damaged lysosomal membranes. Leakage from perforated lysosomes induces the proton sensitive V-ATPase-dependent recruitment of ATG16L1-ATG5-ATG12 complexes, or the calcium-sensitive sphingomyelin-dependent recruitment of TECPR1-ATG5-ATG12 complexes. In both cases, the E3-like complex-dependent ATG5-ATG12 conjugate is required for ESCRT recruitment to the damaged membrane, and stabilization of the ESCRT machinery. Collectively, this study establishes the ATG8 E3-like ligases as membrane damage sensors for ESCRT-mediated membrane repair.
    Keywords:  ATG8 E3-like Ligases; CASM; ESCRT; Lysosomal Membrane Integrity; Membrane Damage Sensor
    DOI:  https://doi.org/10.1038/s44318-025-00672-1
  14. J Cell Biol. 2026 Mar 02. pii: e202506139. [Epub ahead of print]225(3):
    Plasma membrane-to-lysosome FGR signaling regulates endocytosis-associated lysosome homeostasis.
    Qiuyuan Yin, Jifan Qian, Xiao Ding, Xiaoxia Ren, Shalan Li, Zonghao Zhang, Meijiao Li, Long Xiao, Zhiguo Zhang, Fan Lai, Xuna Wu, Xiaojiang Hao, Chonglin Yang.
      Transcriptional control of lysosome biogenesis is an important mechanism underlying cellular adaptation to stress. It is largely unclear how cell surface changes or signals induce alteration in lysosome numbers. By developing a Caenorhabditis elegans-based heterologous TFE3 activation system, we here identify the non-receptor tyrosine kinases SRC-1/-2 (C. elegans) and FGR (mammals) as critical regulators of lysosome biogenesis. In C. elegans, inactivation of src-1/-2 leads to nuclear enrichment of ectopically expressed TFE3 and increased intensity of lysosomal markers. In mammalian cells, FGR inhibition or deficiency similarly results in TFEB/TFE3-dependent lysosomal increase. FGR acts through AKT2 by promoting the activation of the latter. FGR associates with the plasma membrane but is internalized onto endosomes and reaches lysosomes along the endosome-lysosome pathway following endocytosis. Lysosomal FGR promotes AKT2 recruitment to lysosomes, where it phosphorylates TFEB/TFE3 to prevent their activation. Together, these findings reveal a plasma membrane-to-lysosome signaling axis that is required for endocytosis-associated lysosome homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202506139
  15. bioRxiv. 2025 Dec 22. pii: 2025.12.20.695720. [Epub ahead of print]
    Treatment of Huntington's disease with a pan-HTT-targeting CRISPR nuclease.
    Katherine Tan, Daniela Del Bosque Siller, Alisha Y Xiong, Anna X A Wang, Tristan X McCallister, Sreya Mummadi, Luke A St John, Tae Kyu Lee, Annika Carrillo, Daniel G Renshaw, Richard H Zhou, Colin K W Lim, Jack He, Christopher J Fields, Michael R Hayden, Thomas Gaj.
      Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which leads to a mutant protein that destroys neurons in the brain. Despite intense effort, there remains no approved disease-modifying therapy for HD. Here we develop a pan-HTT-targeting CRISPR-Cas9 system that, when delivered to the striatum of R6/2 and YAC128 mice by AAV5, lowered mutant HTT mRNA and protein by 55-80% via its induction of frameshift-inducing indel mutations in HTT exon 1. Cas9 targeting improved motor coordination and locomotor activity, decreased anxiety-like deficits, reduced clasping and weight loss, limited striatal atrophy, and decreased the formation of intranuclear inclusions immunoreactive for the mutant HTT protein. In Hu21/21 mice, which carry the wild-type human HTT gene in lieu of the mouse ortholog, Cas9 lowered the HTT protein by 44% but induced no measurable behavioral deficits and had no adverse effect on neuronal viability, though its targeting was associated with neuroinflammation. Altogether, our results demonstrate the ability for a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provides insights into its tolerability.
    DOI:  https://doi.org/10.64898/2025.12.20.695720
  16. Cell Res. 2026 Jan;36(1): 11-37
    Mitophagy in the pathogenesis and management of disease.
    Qi Wang, Yu Sun, Terytty Yang Li, Johan Auwerx.
      Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy - from receptors and stress-responsive triggers to lysosomal degradation - illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.
    DOI:  https://doi.org/10.1038/s41422-025-01203-7
  17. J Cell Sci. 2026 Jan 01. pii: jcs263847. [Epub ahead of print]139(1):
    Mitochondrial dynamics and signaling in stem cell differentiation.
    Rahul Kumar Verma, Somya Madan, Richa Rikhy.
      Mitochondrial dynamics are defined by the continuous processes of fusion and fission that regulate mitochondrial shape, distribution and activity. They are also involved in cellular functions of mitochondria, such as energy production, metabolic adaptation, apoptosis and cellular stress responses. Consequently, these organelle dynamics play a crucial role in development, growth, differentiation and disease. Mitochondrial morphology is controlled by Drp1 (also known as DNM1L) and Fis1, which drive fission, whereas Opa1, Mfn1 and Mfn2 mediate fusion. The transcription, activation and degradation of these proteins are often regulated by signaling cascades that are crucial for stem cell maintenance and differentiation. In turn, mitochondrial dynamics regulate key outcomes of these pathways. We explore the interplay between mitochondrial fusion and fission proteins and such signaling pathways, including Notch, receptor tyrosine kinase, JNK, Hippo and mTOR signaling, finding that stem cell renewal and differentiation states are dependent on the regulation of signaling pathways by mitochondrial morphology and activity. Overall, this Review highlights how mitochondrial morphology and activity crucially regulate stem cell division for renewal and differentiation, examining their impact across diverse systems.
    Keywords:  Drp1; Marf; Mfn; Mitochondria; Opa1; Signaling; Stem cells
    DOI:  https://doi.org/10.1242/jcs.263847
  18. Cells. 2025 Dec 19. pii: 6. [Epub ahead of print]15(1):
    Genetic Modeling of Lysosomal Storage Disorders (LSDs) in the Brain-Midgut Axis of Drosophila melanogaster During Aging.
    Sophia P Markaki, Nikole M Kiose, Zoi A Charitopoulou, Stylianos Kougioumtzoglou, Athanassios D Velentzas, Dimitrios J Stravopodis.
      Lysosomal storage disorders (LSDs) are a group of rare inherited diseases caused by mutations in the genes encoding the proteins involved in normal lysosomal functions, leading to an accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. The development of powerful and reliable animal model systems that can in vivo recapitulate human LSD pathologies is critical for understanding disease mechanisms and advancing therapeutic strategies. In this study, we identified the Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain-midgut axis via the use of GAL4/UAS and RNAi combined technologies. Transgenic fly models presented key features of human LSD pathologies, including significantly shortened lifespans and a progressive locomotor decline that serves as a measure for neuromuscular disintegration, following age- and sex-dependent patterns. These phenotypic parallels in pathology strongly support the functional relevance of the selected orthologs and underscore the value of Drosophila as a versatile in vivo model system for advanced LSD pathology research, offering state-of-the-art genetic tools for molecularly dissecting disease mechanisms and providing cutting-edge novel platforms for high-throughput genetic and/or pharmacological screening, moving towards development of new therapeutically beneficial drug-based regimens and mutant gene-rescue schemes.
    Keywords:  Drosophila melanogaster; Fabry disease; GAL4/UAS; Gaucher disease; Hunter syndrome; Hurler syndrome; Niemann–Pick disease; Pompe disease; RNAi; Sly disease; Tay–Sachs/Sandhoff disease(s); aging; brain; midgut
    DOI:  https://doi.org/10.3390/cells15010006
  19. Cell Stem Cell. 2026 Jan 08. pii: S1934-5909(25)00442-4. [Epub ahead of print]33(1): 44-57.e7
    Transcriptional code for circuit integration in the injured brain by transplanted human neurons.
    Zhifu Wang, Danyi Zheng, Shu-Min Chou, Phil Jun Kang, Fei Ye, Su-Chun Zhang.
      Neural transplantation holds the potential to repair damaged neural circuits in neurological diseases. However, it remains unknown how the grafted neurons project axons to and make functional connections with the appropriate targets to repair the damaged circuit at the adult stage. Here, we report that human cortical progenitors, transplanted into the ischemic mouse motor cortex, matured and integrated into cortical and subcortical neural circuits, including the corticospinal tract. Neuronal tracing combined with single-nuclei RNA sequencing revealed the close relationship between the transcription profiles of a cortical neuronal subtype, especially those of axon guidance and synapse assembly, with the specific target projection and synapse organization. Machine learning-based regression further identified the transcriptional codes for the targeted projection and circuit integration to reconstruct the damaged circuits. Our finding opens a promising strategy for treating neurological diseases through promoting regeneration and neural transplantation.
    Keywords:  circuit integration code; corticospinal tract; human pluripotent stem cell-derived neuron; neural circuit integration; neural transplantation; neurological disorders; neuronal replacement; stroke
    DOI:  https://doi.org/10.1016/j.stem.2025.12.008
  20. bioRxiv. 2025 Dec 22. pii: 2025.12.19.695531. [Epub ahead of print]
    Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.
    Weijia Zhong, Carlo Scialò, Beatrice Gatta, Manon Häfliger, Noemi Leu, Flavio Lurati, Martina Peter, Nandini Ramesh, Bernd Roschitzki, Somanath Jagannath, Ruchi Manglunia, Elena de Cecco, Su Min Lim, Oscar G Wilkins, Adriano Aguzzi, Michael Ward, Pietro Fratta, Leonard Petrucelli, Clotilde Lagier-Tourenne, Magdalini Polymenidou.
      Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.
    DOI:  https://doi.org/10.64898/2025.12.19.695531
  21. Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2517110123
    Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice.
    Chunyu Chen, Liliang Zhu, Wenxi Li, Yuefeng Jiang, Zhe Zhang, Yongjuan Zhao, Jinzhong Lin, Wei Yu.
      Diabetic peripheral neuropathy (DPN), the most common complication of diabetes, lacks effective treatments and is characterized by early axonal degeneration mediated by sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1). Here, we identify a regulatory mechanism of SARM1's NAD+-cleaving activity via acetylation at lysine 641 (K641). In high-glucose conditions, SIRT3 deacetylates SARM1 at K641, enhancing its NAD+ cleavage activity and exacerbating axonal damage. In type 2 diabetic (T2DM) mice, acetylation of SARM1 at K641 (K641Ac) or Sirt3 knockout mitigates hypoalgesia, intraepidermal nerve fiber loss in footpad skin, and axonal growth retardation in dorsal root ganglia. These interventions also attenuate ROS accumulation, ATP depletion, and NAD+ decline, conferring protection against DPN pathology. Notably, wild-type SARM1 expression reverses the protective effects of Sirt3 ablation in T2DM mice, whereas SARM1 K641Q does not. Our findings establish that SIRT3-mediated deacetylation of SARM1 at K641 drives axonal degeneration in DPN, and enhancing K641 acetylation mitigates disease progression. This study uncovers a critical posttranslational regulation of SARM1 and suggests that targeting the SIRT3-SARM1 axis may offer therapeutic potential for DPN and related neurodegenerative conditions.
    Keywords:  SARM1; acetylation; axonal degeneration; diabetic peripheral neuropathy
    DOI:  https://doi.org/10.1073/pnas.2517110123
  22. Stem Cell Reports. 2026 Jan 02. pii: S2213-6711(25)00358-3. [Epub ahead of print] 102754
    Aβ plaques induce local pre-synaptic toxicity in human iPSC-derived neuron xenografts.
    Jacqueline Fréderique Maria van Vierbergen, Carles Calatayud, Sriram Balusu, Nicolò Carrano, Nicolas Peredo, Katlijn Vints, Sandra Fernández Gallego, Katrien Horré, Bart De Strooper, Patrik Verstreken.
      Xenotransplantation enables the interrogation of human neuron-specific vulnerabilities to Alzheimer's pathology within a physiologically relevant in vivo context. While amyloid-beta (Aβ) is known to disrupt synaptic integrity, it remains uncertain whether the synaptotoxicity observed in vitro accurately models the disease. Here, we establish a xenotransplantation paradigm in which human neurons integrate into the brains of amyloid precursor protein (APP) transgenic mice that develop amyloid plaques. Using a genetically encoded pre-synaptic reporter, we label human pre-synapses post engraftment to assess early-stage pathology. We demonstrate that extracellular Aβ plaques induce localized synaptic damage in human neurons, characterized by local pre-synaptic loss and the formation of dystrophic neurites. Notably, this pathology is restricted to the plaque microenvironment and does not result in widespread pre-synaptic degeneration. Our findings establish this human-mouse chimera model as a platform for dissecting Aβ-induced synaptic pathology and reveal that extracellular Aβ exerts compartmentalized yet impactful toxicity on human pre-synapses.
    Keywords:  Alzheimer’s disease; amyloid-beta plaque; dystrophic neurite; extracellular Aβ; pre-synapse; synapse toxicity; xenotransplantation
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102754
  23. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)00980-3. [Epub ahead of print]86(1): 135-149.e9
    Membrane-protein-mediated phase separation orchestrates organelle contact sites.
    Christian Hoffmann, Takahiro Nagao, Taka A Tsunoyama, Johannes Vincent Tromm, Chinyere Logan, Koki Nakamura, Han Wang, Frans Bianchi, Geert van den Bogaart, Akihiro Kusumi, Yusuke Hirabayashi, Dragomir Milovanovic.
      Mitochondria and the endoplasmic reticulum (ER) contain large areas that are in close proximity. Yet the mechanism of how these inter-organellar adhesions are formed remains elusive. Tight functional connections, termed "membrane contact sites," assemble at these areas and are essential for exchanging metabolites and lipids between the organelles. Recently, the ER-resident protein PDZ domain-containing protein 8 (PDZD8) was identified as a tether between the ER and mitochondria or late endosomes/lysosomes. Here, we show that PDZD8 can undergo phase separation via its intrinsically disordered region (IDR). Endogenously labeled PDZD8 forms condensates on membranes both in vitro and in mammalian cells. Electron microscopy analyses indicate that the expression of full-length PDZD8 rescues the decrease in inter-organelle contacts in PDZD8 knockout cells but not PDZD8 lacking its IDR. Together, this study identifies that PDZD8 condensates at the lipid interfaces act as an adhesive framework that stitches together the neighboring organelles and supports the structural and functional integrity of inter-organelle communication.
    Keywords:  PDZD8; biomolecular condensates; endoplasmic reticulum; liquid-liquid phase separation; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.006
  24. Eur J Cell Biol. 2025 Dec 24. pii: S0171-9335(25)00053-6. [Epub ahead of print]105(1): 151528
    Mutations in the Rab33b protein that lead to the skeletal disease Smith-McCort dysplasia result in unstable proteins and altered autophagy function.
    Sofia R Parisi, Danielle Z Harte, Jeremy C Simpson.
      The human skeletal disease Smith McCort dysplasia is known to be caused by mutations in the RAB33B gene. Despite there being detailed genetic and medical studies about the patients carrying these mutated genes, there is a paucity of information about these mutations at the molecular and cellular level. The RAB33B gene encodes the small GTP binding protein Rab33b, which primarily localises to the Golgi apparatus in cells, and plays roles in membrane traffic and autophagy. In recent years, several different mutations in the RAB33B gene have been reported, potentially giving rise to both prematurely truncated proteins and also proteins containing single amino acid substitutions. Importantly, no work to date has examined the consequences of expression of these Rab33b variants in cells. In the study presented here we use a model cell culture system to seek to understand what the consequences might be to cells expressing five of the reported disease-causing Rab33b variants. We specifically examine the ectopic expression of two truncated and three single amino acid substitution variants in cultured cells. Our results reveal that all of these mutants show subcellular mislocalisation and fail to accumulate on Golgi membranes. We also demonstrate that each of these mutants are unstable and suffer from premature degradation in cells. Finally, overexpression of the single amino acid substitution variants in cells induced for autophagy causes a severe reduction in the number of autophagosomes as defined by the number of LC3B-positive puncta. Our results provide the first molecular insight into the cellular effects caused by five of the reported Rab33b mutants that give rise to Smith McCort dysplasia.
    Keywords:  Autophagy; Golgi; Membrane traffic; Rab proteins; Rab33b; Skeletal dysplasia; Smith-McCort dysplasia
    DOI:  https://doi.org/10.1016/j.ejcb.2025.151528
  25. Stem Cell Res. 2025 Dec 19. pii: S1873-5061(25)00242-9. [Epub ahead of print]90 103892
    Generation of two human iPSC lines from fibroblasts of BPAN patients carrying pathogenic variants in the WDR45 gene.
    Gemma Gasparini, Carolin Kraus, Ejona Rusha, Tanja Orschmann, Saskia B Wortmann, Johannes H Mayr, Anna Ardissone, Arcangela Iuso.
      Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare X-linked dominant disorder (ORPHA:329284) characterized by brain iron accumulation, developmental delay, seizures, motor dysfunction, and progressive neurodegeneration. It results from pathogenic variants inWDR45, encoding WDR45/WIPI4, a key autophagy protein. No curative treatment exists; management is supportive. As BPAN pathogenesis remains unclear, research aims to elucidate its molecular mechanisms and develop targeted therapies. We generated and characterized two induced pluripotent stem cell (iPSC) lines from BPAN patient fibroblasts, providing essential models for studying disease mechanisms and developing effective therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.scr.2025.103892
  26. Mol Brain. 2026 Jan 09.
    Primary cortical neurons precipitate and extrude large mitochondria-associated calcium-phosphate sheets with a bone-precursor-like ultrastructure.
    Erik D Anderson, Christopher A Cronkite, Philip R Baldwin, Carlota P Abella, Joseph G Duman, Ashleigh N Simmonds, M Neal Waxham, Kimberley F Tolias, Steven J Ludtke.
      Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzheimer's disease and Leigh syndrome. The nexus of pathologic extracellular CaP in the nervous system is not well understood, but prior evidence suggests mitochondria could be a source. We have observed mitochondria-sized sheet-like CaP aggregates within functional wild type cortical neuron cultures at 1 and 20 days in vitro. Neurons were extracted from embryonic day 18 (E18) rat embryos following standard protocols to study neuronal structure and function. We have used a combination of cryo-ET, cryo-CLEM, and LDSAED to demonstrate that these aggregates are octacalcium phosphate-like, are associated with mitochondria, and that at least a portion are extruded via migrasomes. Visually similar aggregates were previously observed in Huntington's disease model neurons, but in that study they were not observed in WT controls. These findings show that this CaP aggregation process occurs routinely in WT neurons and may reveal an important link for how mitochondria may participate in calcification, highlighting them as potential therapeutic targets in neurological disorders characterized by pathological calcification, such as Alzheimer's disease.
    Keywords:  Calcium-phosphate; Cryo-CLEM; Cryo-ET; LDSAED; Migrasomes; Mitochondria; Neurons
    DOI:  https://doi.org/10.1186/s13041-025-01272-0
  27. Ann Med Surg (Lond). 2026 Jan;88(1): 1144-1145
    AMT-130 gene therapy: a promising disease-modifying approach for Huntington's disease.
    Chisanga Mwape, Afnan Ahmad Qureshi, Muhammad Zaid Saeed, Aleeza Fatima, Aiman Jamil, Huzaifa Mahmood, Ailiya Batool, Abdul Moiz Khan.
      Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by expanded Cytosine-Adenine-GuanineCAG repeats in the huntingtin (HTT) gene, leading to the production and accumulation of mutant huntingtin protein and subsequent neuronal dysfunction and loss. Current management remains largely symptomatic, with no established disease-modifying therapy. AMT-130 represents a novel and promising approach aimed at directly targeting the underlying molecular pathology of HD. AMT-130 is a one-time gene therapy that utilizes an adeno-associated virus serotype 5 (AAV5) vector to deliver an engineered microRNA (miHTT) into the caudate and putamen via stereotactic intracerebral infusion. This microRNA selectively reduces HTT mRNA levels, resulting in sustained lowering of mutant huntingtin protein. Preclinical studies in both large-animal and rodent models have demonstrated broad vector distribution, long-term expression, significant reduction in huntingtin levels, improved motor performance, decreased neuronal degeneration, and prolonged survival. Early Phase I/II clinical data indicate a favorable safety profile, reductions in neurofilament light chain levels, and stabilization of motor and functional decline, particularly in high-dose cohorts, suggesting a potential slowing of disease progression. While long-term efficacy and broader clinical validation are still required, AMT-130 shows strong potential to shift HD treatment from purely symptomatic care toward meaningful disease modification. Its success may also pave the way for microRNA-based therapies in other neurodegenerative disorders.
    Keywords:  AMT-130; Huntington’s disease; gene therapy; microRNA; neurodegeneration
    DOI:  https://doi.org/10.1097/MS9.0000000000004574
  28. Autophagy. 2026 Jan 04. 1-18
    Measuring lysosome damage and lysophagy in vivo.
    Zelai Wu, Hanyu Zhan, Zhiming Huang, Changjing Wang, Boran Li, Yepeng Hu, Zhida Chen, Wei Liu, Weihua Gong, Yongjuan Sang, Qiming Sun.
      Lysosome homeostasis is vital for cellular fitness due to the essential roles of this organelle in various pathways. Given their extensive workload, lysosomes are prone to damage, which can stimulate lysosomal quality control mechanisms such as biogenesis, repair, or autophagic removal - a process termed lysophagy. Despite recent advances highlighting lysophagy as a critical mechanism for lysosome maintenance, the extent of lysosome integrity perturbation and the magnitude of lysophagy in vivo remain largely unexplored. Additionally, the pathophysiological relevance of lysophagy is poorly understood. To address these gaps, it is necessary to develop quantifiable methods for evaluating lysosome damage and lysophagy flux in vivo. To this end, we created two transgenic mouse lines expressing a tandem fluorescent LGALS3/galectin 3 probe (tfGAL3), either constitutively or conditionally under Cre recombinase control, utilizing the property of LGALS3 to recognize damaged lysosomes. This tool enables spatiotemporal visualization of lysosome damage and lysophagy activity at single-cell resolution in vivo. Systemic analysis across various organs, tissues, and primary cultures from these lysophagy reporter mice revealed significant variations in basal lysophagy, both in vivo and in vitro. Additionally, this study identified substantial changes in lysosome integrity and lysophagy flux in different tissues under stress conditions such as starvation, acute kidney injury and diabetic modeling. In conclusion, these complementary lysophagy reporter models are valuable resources for both basic and translational research.Abbreviation: AAV: adeno-associated virus; ATG7: autophagy related 7; CA-tfGAL3: cre-recombinase-activated tandem fluorescent LGALS3; DAPI: 4',6-diamidino-2-phenylindole; DM: diabetes mellitus; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HFD: high-fat diet; Igs2/H11/Hipp11: intergenic site 2; IST1: IST1 factor associated with ESCRT-III; KI: knock-in; LAMP1: lysosomal-associated membrane protein 1; LGALS3: lectin, galactoside-binding, soluble, 3; LLOMe: L-leucyl-L-leucine methyl ester hydrobromide; MEFs: mouse embryonic fibroblasts; NaOx: sodium oxalate; PDCD6IP: programmed cell death 6 interacting protein; PTECs: proximal tubular epithelial cells; RFP: red fluorescent protein; STZ: streptozotocin; TAM: tamoxifen; tfGAL3: tandem fluorescent LGALS3; TMEM192: transmembrane protein 192.
    Keywords:  In vivo; lysophagy; lysosome; lysosome damage; ratiometric probe
    DOI:  https://doi.org/10.1080/15548627.2025.2608974
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒18 at 18:46.