bims-axbals 2026-01-04 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–01–04
sixteen papers selected by
TJ Krzystek

Spinal Spheroids as Screening Platform for Peripheral Neuropathies.
LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.
Huntington's disease-associated ankyrin repeat palmitoyl transferases are rate-limiting factors in lysosome formation and fusion.
Mapping spatial organization of in vitro neuronal networks using high-content imaging.
A lysosomal surveillance response promotes healthspan in C. elegans.
Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions.
Stem cell derived neural organoid approaches for neurological diseases.
Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study.
Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.
Self-renewal of neuronal mitochondria through asymmetric division.
DEAF1 - a transcriptional brake on muscle autophagy.
Targeting Cathepsins in Neurodegeneration: Biochemical Advances.
Imaging Dynamic Subcellular Organization at High Spatiotemporal Resolution.
Therapeutic GSK-3β targeting stabilizes multifunctional β-catenin to rescue neuronal and behavioral deficits in Fragile X Messenger Ribonucleoprotein 1 KO Mice.
A novel mechanism of lysosome-dependent microautophagy of er exit sites.
Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts.

Methods Mol Biol. 2026 ;2989 241-255

Spinal Spheroids as Screening Platform for Peripheral Neuropathies.

Elizabeth H Jacobs, Jessica Medina, Christopher Yanick, Renata Maciel, Mario Saporta.

  The lack of effective disease-modifying therapies for axonopathies highlights the need for novel preclinical models suitable for treatment development. Two-dimensional neuronal cultures lack the directional axonal distribution required to investigate length-dependent processes such as peripheral neuropathies. To optimize this well-established model system, we developed a robust human platform to study axonal morphology and physiology based on three-dimensional motor neuron cultures (i.e., spinal spheroids). We differentiate motor neurons from human induced pluripotent stem cells, purify them by magnetic sorting, and culture them in suspension until they form spheroids. Axons are allowed to grow out of plated spinal spheroids in a radial fashion at an average rate of 200 micrometers/day and reach up to 1 cm in length. This system is optimized for morphological analysis, including high content imaging, investigation of axonal protein expression, and time-lapse imaging of axonal transport.

Keywords:  Charcot-Marie-Tooth disease; High content imaging; Induced pluripotent stem cells; Motor neurons; Neuropathy; Spinal spheroids

DOI:  https://doi.org/10.1007/978-1-0716-4985-5_12
PLoS Genet. 2025 Dec;21(12): e1012007

LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.

Shreevidya Korada, Oliver H Tam, Hunter C Greco, Molly Gale Hammell, Josh Dubnau, Roger B Sher.

A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs/ERVs are mobile virus-like genetic elements that constitute about 45% of our genome and encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. A causal role of RTEs/ERVs has been demonstrated in Drosophila in mediating both intracellular toxicity of TDP-43 and the intercellular spread of toxicity from glia to neurons. RTEs/ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer's Disease (AD) patients, but the role of RTEs/ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. We utilized established transgenic mouse models that overexpress moderate levels of human wild-type TDP-43 or a mutant version with a specific ALS-causal Q331K amino acid substitution, together with a LINE-1-EGFP retrotransposon indicator line. We found that TDP-43 animals exhibit broad expression of RTEs/ERVs with LINE-1 retrotransposition in glia and neurons in the motor cortex. Expression begins with onset of neurological phenotypes, earlier in hTDP-43-Q331K animals and later in hTDP-43-WT. The LINE-1-EGFP retrotransposition reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms, while EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with cell non-autonomous effects on nearby neurons and glial cells.

DOI: https://doi.org/10.1371/journal.pgen.1012007
PLoS Genet. 2025 Dec 31. 21(12): e1011607

Huntington's disease-associated ankyrin repeat palmitoyl transferases are rate-limiting factors in lysosome formation and fusion.

Győző Szenci, Attila Boda, Anikó Nagy, Dorottya Károlyi, András Rubics, Zsombor Szőke, Gergő Falcsik, Tibor Kovács, Péter Lőrincz, Gábor Juhász, Szabolcs Takáts.

Protein palmitoylation in the Golgi apparatus is critical for the appropriate sorting of various proteins belonging to secretory and lysosomal systems, and defective palmitoylation can lead to the onset of severe pathologies. HIP14 and HIP14L ankyrin repeat-containing palmitoyl transferases were linked to the pathogenesis of Huntington's disease, however, how perturbation of these Golgi resident enzymes contributes to neurological disorders is yet to be understood. In this study, we investigated the function of Hip14 and Patsas - the Drosophila orthologs of HIP14 and HIP14L, respectively - to uncover their role in secretory and lysosomal membrane trafficking. Using larval salivary gland, a well-established model of the regulated secretory pathway, we found that these PAT enzymes equally contribute to the proper maturation and crinophagic degradation of glue secretory granules by mediating their fusion with the endo-lysosomal compartment. We also revealed that Patsas and Hip14 are both required for lysosomal acidification and biosynthetic transport of various lysosomal hydrolases, and we demonstrated that the rate of secretory granule-lysosome fusion and subsequent acidification positively correlates with the level of Hip14. Furthermore, Hip14 is also essential for proper lysosome morphology and neuronal function in adult brains. Finally, we found that the over-activation of lysosomal biosynthetic transport and lysosomal fusions by the expression of the constitutively active form of Rab2 could compensate for the lysosomal dysfunction caused by the loss of Patsas or Hip14 both in larval salivary glands and neurons. Therefore, we propose that ankyrin repeat palmitoyl transferases act as rate-limiting factors in lysosomal fusions and provide genetic evidence that defective protein palmitoylation and the subsequent lysosomal dysfunction can contribute to the onset of Huntington's disease-like symptoms.

DOI: https://doi.org/10.1371/journal.pgen.1011607
Sci Rep. 2025 Dec 30.

Mapping spatial organization of in vitro neuronal networks using high-content imaging.

Angelica Casotto, Cátia P Frias, Myta Joosten, Selina M W Teurlings, Martijn Schonewille, Geeske M van Woerden, Jos W Zwanikken, Dimphna H Meijer.

Neuronal network formation is an intricate process by which individual neurons connect into a functional circuitry. At the subcellular level, neuronal connectivity is characterized by the number, size and strength of synapses. At the cellular level, in vitro network characterization remains a challenge due to the large number of neurons involved, spreading widely across a culture dish. Here, we demonstrate a pipeline using high-content confocal microscopy and automated image analysis to study spatial organization of individual neurons in an in vitro cellular network. With this approach, we enable analysis of thousands of neurons in one well, and of multiple wells simultaneously. Using this workflow, we compared the spatial organization of primary mouse neuronal networks derived from the hippocampus, cortex and cerebellum. We also demonstrate how to extract morphological details, such as size of the nucleus and axon initial segment number, orientation and length from our data. This workflow can be applied to study underlying molecular mechanisms of circuitry formation, to assess network formation of neurons derived from mouse or human iPSC models for neurological diseases, and serve as a future platform for drug development.

DOI: https://doi.org/10.1038/s41598-025-29250-5
Metabol Open. 2025 Dec;28 100396

A lysosomal surveillance response promotes healthspan in C. elegans.

Liaoyuan Zheng, Junli Liu.

Lysosomes, the cellular recycling hubs, are indispensable for maintaining homeostasis by degrading misfolded proteins, damaged organelles, and foreign pathogens. Their dysfunction is a hallmark of aging and age-related neurodegenerative diseases, where impaired clearance of toxic protein aggregates drives pathogenesis. Nevertheless, the mechanisms by which lysosomal function can be enhanced to mitigate these detrimental processes remain inadequately understood. A recent study conducted by Li et al. describes a newly identified transcriptional program, the Lysosomal Surveillance Response (LySR), that, when activated, significantly extends healthspan and reduces proteotoxicity in C. elegans. This adaptive transcriptional program, governed by the GATA transcription factor, ELT-2, and modulated by the acetyltransferase CBP-1, operates independently of canonical longevity pathways such as the DAF-2 insulin-like signaling. This work not only unveils a previously unrecognized longevity pathway but also charts a new course for developing therapies targeting aging and neurodegeneration.

DOI: https://doi.org/10.1016/j.metop.2025.100396
Traffic. 2026 Mar;27(1): e70026

Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions.

Shanshan Jiang, Jingyi Fu, Shan Li, Zehui Li, Qirui Zhao, Yuqi Yin, Mei Yang, Yonghua Wang.

Lysosomal exocytosis is a fundamental cellular process that involves the fusion of lysosomes with the plasma membrane and the release of lysosomal contents into the extracellular space. This review provides an in-depth analysis of the molecular mechanisms, physiological functions, and disease implications of lysosomal exocytosis, highlighting recent advances and novel aspects. We discuss the intricate molecular machinery that orchestrates lysosomal trafficking, docking, and fusion, as well as the critical roles of lysosomal exocytosis in maintaining cellular homeostasis, facilitating intercellular communication, and contributing to specialized cellular functions. Additionally, the review explores the complex involvement of lysosomal exocytosis in various disease states, including lysosomal storage disorders, neurodegenerative diseases, cancers, and immune system disorders, underlining its potential as a therapeutic target. By identifying current knowledge gaps and providing future research directions, this review aims to stimulate further investigation into the multifaceted nature of lysosomal exocytosis and its implications for human health and disease.

DOI: https://doi.org/10.1111/tra.70026
Neural Regen Res. 2025 Dec 30.

Stem cell derived neural organoid approaches for neurological diseases.

Rosalie Elvira, Xiao-Xue Dong, Alfred Sun Xuyang, Wai Hon Chooi, Huck Hui Ng, Hongyan Wang, Yun-Cheng Wu, Eng King Tan, Zhi Dong Zhou.

  Traditional two-dimensional cultures and animal models often fall short in capturing the complexities of neurodevelopmental and neurodegenerative diseases. However, recently developed neural organoid approaches, three-dimensional structures derived from human pluripotent stem cells, have become powerful tools for modeling human neuronal development and disease. Unlike traditional models, neural organoids provide significant insights and improved modeling capabilities. Here, we explore various types of neural organoids in disease modeling and outline distinct protocols for generating each type, including specific patterning methods, growth factors, and differentiation durations. The potential and advantages of co-culturing neural organoids with other cells and tissues are also discussed. While neural organoids have already made significant contributions to neuroscience research, future directions should focus on enhancing their maturation and functionality. The progression of neural organoids approaches will generate more accurate and comprehensive disease models, ultimately adding to our understanding of disease pathogenesis and paving the way for future precision therapies for neurological diseases.

Keywords:  neural differentiation; neural organoids; neurogenesis; neurological diseases; stem cells; three-dimensional models

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01004
Neurobiol Dis. 2025 Dec 30. pii: S0969-9961(25)00470-X. [Epub ahead of print] 107253

Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study.

Beck Strohmer, Kaitlyn Grosh, Roser Montañana-Rosell, Santiago Mora, Jessica Ausborn, Ilary Allodi.

  Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1-motoneuron connections improved motor function and saved motoneurons in the SOD1G93A ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor-extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1G93A ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.

Keywords:  Amyotrophic Lateral Sclerosis; Central pattern generator; Computational modeling; Gene therapy; Spiking neural network

DOI:  https://doi.org/10.1016/j.nbd.2025.107253
Neuron. 2025 Dec 30. pii: S0896-6273(25)00890-6. [Epub ahead of print]

Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.

Sandeep Kumar Dubey, Divya Chaubey, Chiseko Ikenaga, Wen-Wen Lin, Hugo J Bellen, Thomas E Lloyd.

  Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants cause a reduction in nucleoporins in Drosophila, induced pluripotent stem cell (iPSC)-derived motor neurons, and muscle biopsies from patients, indicating a dominant gain-of-function mechanism. Mechanistically, disease-associated mutations in VCP result in increased recruitment to NPCs through interactions with Ufd1-Npl4, leading to the removal of a subset of nucleoporins from NPCs and disrupting NCT. These findings show that the VCP-Ufd1-Npl4 pathway regulates NPC quality control and that disease-associated variants aberrantly activate the VCP-Ufd1-Npl4 complex to degrade NPCs and disrupt NCT.

Keywords:  ALS; Drosophila; TDP-43; VCP; muscle disease; neurodegeneration; nuclear pore complex; nucleocytoplasmic transport; nucleoporin; protein quality control

DOI:  https://doi.org/10.1016/j.neuron.2025.11.017
bioRxiv. 2025 Dec 18. pii: 2025.12.17.694973. [Epub ahead of print]

Self-renewal of neuronal mitochondria through asymmetric division.

Tejashree Pradip Waingankar, Camryn Zurita, Angelica E Lang, Cliff Vuong, Ahmad Shami, Diana Bautista, Catherine Drerup, Samantha C Lewis.

Mitochondrial ATP production is essential for life. Mitochondrial function depends on the spatio-temporal coordination of nuclear and mitochondrial genome expression, yet how this coordination occurs in highly polarized cells such as neurons remains poorly understood. Using high-resolution imaging in mouse peripheral sensory neurons and zebrafish larvae, we identified a sub-population of mitochondria enriched in mtDNA that are positioned at the collateral branch points of long sensory neurites, both in vitro and in vivo . While the mitochondria in neurites are generally depleted of mtDNA, those at axon branch points preferentially engage in mtDNA replication and transcription, accumulate nuclear-encoded mitochondrial mRNA, and are spatially linked to nascent cytosolic peptide synthesis. The mtDNA-positive mitochondrial pool exhibits asymmetric genome partitioning at division, shedding highly motile daughters that lack mtDNA. Asymmetric division rejuvenates the membrane potential of the mtDNA-rich, biogenesis-dedicated mitochondria. We also found that, in peripheral sensory neurons, axonal mitochondria rarely fuse or share matrix contents, explaining how differentiated daughters maintain their distinct composition and fate after fission. Thus, division-coupled mitochondrial self-renewal is yoked to neurite topology in sensory neurons, patterning mitochondrial diversity and homeostasis from micron to meter scales.

DOI: https://doi.org/10.64898/2025.12.17.694973
Autophagy. 2025 Dec 31. 1-2

DEAF1 - a transcriptional brake on muscle autophagy.

Wen Xing Lee, Kah Yong Goh, Sze Mun Choy, Hong-Wen Tang.

  Macroautophagy/autophagy protects muscle from proteotoxic stress and maintains tissue homeostasis, yet skeletal muscle relies on it more than most organs. Adult fibers endure constant mechanical strain and require continuous turnover of long-lived proteins, while muscle stem cells (MuSCs) depend on autophagy to remain quiescent, activate after injury, and regenerate effectively. How autophagy is transcriptionally regulated in muscle has been unclear. We identified DEAF1 as a transcriptional brake on autophagy. In MuSCs, DEAF1 controls activation and regeneration and becomes aberrantly elevated with age, promoting protein aggregate formation and cell death. In muscle fibers, DEAF1 is chronically induced during aging, suppressing autophagy and driving functional decline. Exercise reverses DEAF1 induction, restoring autophagy and muscle function. These findings reveal DEAF1 as a key regulator linking autophagy to regeneration and aging, highlighting a therapeutically tractable axis for preserving muscle health.

Keywords:  Autophagy; DEAF1; muscle; muscle stem cell; regeneration

DOI:  https://doi.org/10.1080/15548627.2025.2610451
Biomedicines. 2025 Dec 09. pii: 3019. [Epub ahead of print]13(12):

Targeting Cathepsins in Neurodegeneration: Biochemical Advances.

Francesca Di Matteo, Mariapia Vietri, Simone D'Alessio, Tania Ciaglia, Erica Federica Vestuto, Giacomo Pepe, Ornella Moltedo, Veronica Di Sarno, Simona Musella, Carmine Ostacolo, Fabio Cominelli, Pietro Campiglia, Alessia Bertamino, Maria Rosaria Miranda, Vincenzo Vestuto.

  Background/Objectives: Cathepsins, lysosomal proteases crucial for neuronal proteostasis, mediate the clearance of misfolded and aggregated proteins. Their dysregulation is implicated in neurodegenerative and neuropsychiatric disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. These conditions are characterized by toxic protein accumulation and impaired clearance, which exacerbate cellular stress responses, including the unfolded protein response (UPR), oxidative damage, and mitochondrial dysfunction. This review aims to summarize current knowledge on cathepsin roles in these pathways and assess their therapeutic potential. Methods: A comprehensive literature review was conducted, focusing on recent in vitro and in vivo studies investigating cathepsin function, inhibition, and modulation. Mechanistic insights and pharmacological approaches targeting cathepsins were analyzed, with attention to challenges in translating preclinical findings to clinical settings. Results: Cathepsins demonstrate a dual role: their proteolytic activity supports neuronal health by degrading toxic aggregates, but altered or insufficient activity may worsen proteotoxic stress. Studies reveal that cathepsins regulate autophagy, apoptosis, and neuroinflammation both intracellularly and extracellularly. Despite promising mechanistic data, clinical translation is hindered by issues such as poor inhibitor selectivity, limited brain penetration, and variability across preclinical models. Conclusions: Targeting cathepsins presents a promising strategy for treating neurodegenerative and neuropsychiatric disorders, but significant challenges remain. Future research should focus on improving drug specificity and delivery, and on developing standardized models to better predict clinical outcomes.

Keywords:  ER stress; biochemical pathways; cathepsin inhibitors; cathepsins; drug development; mitochondrial disfunction; neurodegeneration; neurodegenerative disease

DOI:  https://doi.org/10.3390/biomedicines13123019
Annu Rev Biophys. 2026 Jan 02.

Imaging Dynamic Subcellular Organization at High Spatiotemporal Resolution.

Francesca W van Tartwijk, Liuba Dvinskikh, Edward N Ward, Meng Lu, Clemens F Kaminski.

The spatiotemporal organization of intracellular compartments is fundamental to cellular function and to the understanding of the processes underpinning health and disease. Fluorescence microscopy offers a powerful means to observe organelle morphology and dynamics with high specificity. However, no single technique can capture the wide range of relevant spatiotemporal scales due to inherent trade-offs in resolution, speed, field of view, signal-to-noise ratio, and sample viability. In this review, we describe recent developments across high-resolution fluorescence microscopy techniques and associated computational methods, critically evaluating how these advances address key limitations. Through biological examples of organelle dynamics at different scales, we illustrate the impact of these technologies on our understanding of cellular organization and function. Finally, we discuss the current challenges and outline future directions for imaging-based research, highlighting the potential for further innovations to deepen insights into dynamic subcellular processes.

DOI: https://doi.org/10.1146/annurev-biophys-021424-011728
Brain Res Bull. 2025 Dec 30. pii: S0361-9230(25)00522-2. [Epub ahead of print] 111710

Therapeutic GSK-3β targeting stabilizes multifunctional β-catenin to rescue neuronal and behavioral deficits in Fragile X Messenger Ribonucleoprotein 1 KO Mice.

Siming Zhang, Peng Xiang, Mingjiao Suo, Ziyu Yi, Zhen Wei, Jinquan Li, Yan Zeng, Yushan Chen.

  Fragile X syndrome (FXS) stands as the predominant single gene mutation pathogenic factor linked to autism spectrum disorder (ASD), and it constitutes an inherited intellectual disability rooted in the disruption of fragile X messenger ribonucleoprotein 1 gene (FMR1). The neurodevelopmental disorder is characterized by synaptic dysfunction manifesting as the impairment of cognitive function and social communication. Wnt/β-catenin pathway plays a pivotal role in regulating synaptic structural remodeling and functional homeostasis, critically contributing to higher-order neural processes such as learning and memory. Studies have identified glycogen synthase kinase 3 beta (GSK3β), a key negative regulator of Wnt signal transduction, is abnormally activated in the pathophysiology of FXS, and demonstrated that GSK3β inhibition partially rescues cognitive and behavioral deficiencies in FXS mice. However, the spatiotemporal dysregulation of β-catenin dynamics and its synaptic consequences remain poorly understood. In this study, we aim to investigate the role and molecular mechanism of Wnt/β-catenin pathway during the developmental stages of FXS. Fmr1 gene knockout (Fmr1 KO) mice were utilized as a model for FXS. We systematically explored β-catenin homeostasis across subcellular compartments. Our results showed that there was an increased phosphorylation of β-catenin at Ser33,37, Thr41 and Ser552 residues, which foster its degradation. This was accompanied by reduced levels of active β-catenin in the membrane, cytoplasm and nucleus within the hippocampus (Hipp) and prefrontal cortex (PFC) of Fmr1 KO mice. Confocal microscopy further demonstrated diminished co-localization of β-catenin with N-cadherin, leading to compromised intercellular adhesion in both Fmr1 KO neurons. Moreover, FXS mice showed impaired neuronal morphology and deficiencies in social and cognitive functions, which are associated with the downregulation of pre- and postsynaptic proteins targeted by Wnt pathway. Strikingly, pharmacological activation of Wnt signal transduction restored β-catenin nuclear translocation and synaptic protein expression, rescuing neuronal ultrastructural abnormalities and improving cognitive and social behaviors. Our findings establish hypoactivity of canonical Wnt signaling as a central mechanism underlying synaptic pathology in FXS, linking β-catenin destabilization to altered neuronal morphology, aberrant synaptic protein networks, and behavioral phenotypes. Consequently, bolstering Wnt pathway may represent a promising neuroprotective strategy for precision intervention in FXS.

Keywords:  Fmr1; Fragile X syndrome; Wnt/β-catenin pathway; neuronal morphology; presynaptic and postsynaptic protein

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111710
Autophagy. 2025 Dec 31.

A novel mechanism of lysosome-dependent microautophagy of er exit sites.

Dibyendu Bhattacharyya, Daniel J Klionsky.

  Endoplasmic reticulum (ER) exit sites (ERES) serve as essential hubs for the packaging and export of secretory proteins into the COPII vesicular pathway. Previous studies have shown that ERES are dynamic and capable of adapting to stress, but the molecular details controlling their degradation under nutrient stress conditions were largely unknown. The study by Liao et al. (2024) introduces a new mechanism in which ERES are degraded through lysosome-dependent microautophagy in response to nutrient stress. This process is uniquely facilitated by COPII components, the calcium-binding adaptor ALG2, and the ESCRT machinery. The authors demonstrate that inhibiting MTOR triggers calcium release from lysosomes, which then recruits ALG2, leading to SEC31 ubiquitination and subsequently promoting PDCD6IP/ALIX-ESCRT-dependent lysosomal engulfment of ERES. This research reveals an unexplored pathway for the quality control and recycling of secretory machinery, thereby improving our understanding of ER turnover and establishing a mechanistic link between nutrient sensing, autophagy, and remodeling of the secretory pathway.

Keywords:  Autophagy; COPII; ESCRT; er exit sites; microautophagy

DOI:  https://doi.org/10.1080/15548627.2025.2608387
Neurobiol Dis. 2025 Dec 30. pii: S0969-9961(25)00472-3. [Epub ahead of print] 107255

Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts.

Barbara Pakula, Agata Wydrych, Magdalena Lebiedzinska-Arciszewska, Patrycja Jakubek-Olszewska, Marta Skowrońska, Iwona Kurkowska-Jastrzębska, Justyna Janikiewicz, Aneta M Dobosz, Emre Hakli, Jędrzej Szymański, Paolo Pinton, Agnieszka Dobrzyń, Werner J H Koopman, Mariusz R Wieckowski.

  Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) is the third most common genetically-defined subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), a group of rare, clinically heterogeneous disorders. The MPAN pathomechanism, including the link between C19orf12 mutations, iron accumulation, and metabolic alterations, is still poorly understood. While earlier research pointed to impaired autophagy in MPAN, a comprehensive understanding remains elusive. Here, we investigated the autophagy-linked proteome in primary fibroblasts derived from 18 MPAN patients and identified distinct alterations in autophagy-related protein expression. Importantly, a subset of these proteomic changes showed significant associations with disease severity, highlighting their potential relevance as biomarkers of clinical progression. Functional analyses further revealed increased lysosomal acidification as the most consistently affected autophagy-related process in MPAN fibroblasts. Notably, both proteomic and functional alterations were associated with C19orf12 mutation zygosity, underscoring its modulatory role in disease-relevant cellular pathways.

Keywords:  Autophagy flux; Ferrous iron; Fibroblasts; Lysosomal pH; Mitochondrial membrane protein-associated neurodegeneration; Proteomic analysis; V-ATPase

DOI:  https://doi.org/10.1016/j.nbd.2025.107255