bims-axbals 2026-06-14 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–06–14
28 papers selected by
TJ Krzystek

Human iPSC-derived motor neurons as a platform for elucidating TDP-43-related amyotrophic lateral sclerosis pathogenesis: a mini review.
The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.
ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.
Conditional Knockout of Paxillin in Mouse Cortical Pyramidal Neurons Does Not Impair Axon Outgrowth or Corpus Callosum Size.
From anti-fungal to potential neurotherapeutic: Posaconazole as an effective inhibitor of cellular TDP-43 pathology.
PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model.
Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.
Septins in the Middle-Makers and Breakers of Membrane Contact Sites.
The structural basis for LRRK2's activation and autoinhibition.
Restoring DSCAM expression mitigates neuronal morphology and axon guidance deficits in Down syndrome.
The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?
Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.
VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.
Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on TDP-43 Proteinopathy.
Morphology-robust quantification of subcellular organization in complex cells.
Enhanced Calcium Activity and Transcriptomic Alterations in iPSC-derived Neurons from BAFME Patients with Repeat Expansions.
Loss of astrocytic markers and impaired metabolic function in spinocerebellar ataxia type 7 patient-derived neural cultures.
Mitochondrial Dysfunction as a Driver of Neurodegeneration in Parkinson's and Huntington's Disease: Molecular Insights and Emerging Interventions.
Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.
α-Synuclein and γ-Tubulin Cooperatively Regulate Activity-Evoked Presynaptic Microtubule Nucleation to Gate Dopamine Release.
Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes.
Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse.
Dysregulation of autophagosome-mitochondria contacts contributes to autophagy dysfunction and neurodegeneration in tauopathy.
Suppression of ATM kinase signaling accelerates cellular senescence.
Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.
Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
Quantification of cell viability by automated analysis of live cell imaging.

Front Mol Neurosci. 2026 ;19 1864964

Human iPSC-derived motor neurons as a platform for elucidating TDP-43-related amyotrophic lateral sclerosis pathogenesis: a mini review.

Satoshi Yokoi, Yohei Iguchi, Masahisa Katsuno.

  TAR DNA-binding protein 43 (TDP-43) is a major pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). Heterozygous mutations in TDP-43 cause familial ALS, known as ALS10. TDP-43 is predominantly localized in the nucleus under physiological conditions. Not only ALS patients with TARDBP mutations but also the majority of sporadic ALS patients exhibit TDP-43 pathology, which is defined by nuclear clearance and cytoplasmic aggregation. The inclusion of cryptic exons in genes such as STMN2 and UNC13A has emerged as a hallmark of TDP-43 loss of function, as demonstrated in TDP-43 knockdown models and postmortem analyses. However, it is not yet clear how TDP-43 levels and location change from healthy to pathological conditions in ALS. Motor neurons derived from induced pluripotent stem cells (iPSCs) have been widely used in ALS research and provide a promising platform to investigate early-stage disease mechanisms. However, challenges remain in generating models that faithfully recapitulate ALS pathogenesis. In this review, we summarize recent advances in TDP-43-related iPSC-derived motor neuron models and discuss future perspectives for elucidating ALS pathogenesis. We propose that longitudinal analyses of TDP-43 dynamics and co-culture systems will be essential to better model early ALS pathogenesis.

Keywords:  RNA-binding protein; TDP-43; amyotrophic lateral sclerosis; co-culture; iPSC-derived motor neuron

DOI:  https://doi.org/10.3389/fnmol.2026.1864964
J Neurochem. 2026 Jun;170(6): e70496

The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.

Emma D Turner, Alison E Twelvetrees.

The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.

DOI: https://doi.org/10.1111/jnc.70496
Neurosci Res. 2026 Jun 11. pii: S0168-0102(26)00066-0. [Epub ahead of print] 105079

ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.

Elvira Abzhanova, Yuzuki Kawae, Hiromi Mizuno, Terumasa Umemoto, Halilibrahim Ciftci, Masafumi Tsuboi, Yusuke Hirabayashi, Hidenobu Mizuno.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons that gradually causes muscle weakness and paralysis, eventually resulting in death. While ALS was once believed to specifically target motor neurons, recent clinical studies have revealed sensory involvement. The pathological hallmark of ALS is TAR DNA-binding protein 43 (TDP-43) aggregation in cytoplasm, with increasing evidence of its presence in both motor　and sensory neurons. However, sensory abnormalities remain poorly characterized. To address this research gap, we analyzed the effects of TDP-43 expression on layer 2/3 (L2/3) pyramidal neurons of the primary somatosensory cortex in mice projecting through corpus callosum. In utero electroporation (IUE) was performed to express GFP alone (control) or in combination with TDP-43. Compared with the control, mice co-expressing GFP and TDP-43 showed disturbed callosal axonal projections of L2/3 neurons. Mutant TDP-43 variants displayed a more pronounced phenotype, indicating pathogenic role during fetal cortical development. To distinguish developmental from maintenance effects, tamoxifen-inducible TDP-43 expression was used to initiate postnatal TDP-43 expression. Postnatal induction resulted in shorter axonal length and reduced branching rather than gross projections disturbance. Taken together, these results demonstrate that TDP-43 expression can disturb the integrity of axonal projections, such as callosal projections of L2/3 neurons in the somatosensory cortex.

Keywords:  ALS; TDP-43; axonal projections; corpus callosum; layer 2/3 cortical neurons; neuronal aggregates

DOI:  https://doi.org/10.1016/j.neures.2026.105079
FASEB Bioadv. 2026 May;8(5): e70120

Conditional Knockout of Paxillin in Mouse Cortical Pyramidal Neurons Does Not Impair Axon Outgrowth or Corpus Callosum Size.

Katelyn Rygel, Kasey Gillespie, Kristy Welshhans.

  Axon growth is an essential cellular process during neural development, and its dysregulation contributes to numerous neurodevelopmental disorders. During axon growth, extracellular signals direct neurons to extend projections that connect with their synaptic targets. Paxillin is a key member of adhesion sites that control motility by linking the intracellular actin cytoskeleton to the extracellular matrix. Paxillin also binds to the cytoskeletal protein, tubulin. However, little is known about the role of adhesion proteins in neurons. Here, we use conditional paxillin knockout mice to investigate how the loss of paxillin in pyramidal cortical neurons affects developing neuron morphology. Surprisingly, loss of paxillin in pyramidal cortical neurons caused no change in axon length or soma area between control (Pxn F/F ) and conditional paxillin knockout (Pxn F/F; Emx1-Cre ) mice at basal conditions. Following brain-derived neurotrophic factor stimulation, the loss of paxillin resulted in no change in soma area or axonal β-tubulin levels, but did result in a significant increase in axon length, as compared to control. Finally, the corpus callosum size was not significantly different between Pxn F/F and Pxn F/F; Emx1-Cre animals. In summary, these data suggest that paxillin is not required for axonal growth during neural development.

Keywords:  adhesion; axon growth; neuronal development; paxillin

DOI:  https://doi.org/10.1096/fba.2025-00120
bioRxiv. 2026 Jun 04. pii: 2026.06.01.728552. [Epub ahead of print]

From anti-fungal to potential neurotherapeutic: Posaconazole as an effective inhibitor of cellular TDP-43 pathology.

Noah Nathan Kochen, Sophia Zafari, Aimee Renaud, Nathan Schneider, Nagamani Vunnam, Elly E Liao, James R Dutton, Anthony R Braun, Jonathan N Sachs.

Recently, we showed that ketoconazole, a known anti-fungal inhibitor of CYP51, stabilized TAR DNA-binding protein 43 (TDP-43) native self-interactions, reduced TDP-43 pathology and rescued TDP-43-induced SREBP2 downregulation. Despite its promising effects, ketoconazole is not viable for repurposing for ALS due to liver toxicity side effects that occur when orally delivered. To address this, we tested the activities of seven additional known azole-based CYP51 inhibitors in order identify a viable alternative to ketoconazole. Using our established TDP-43 mislocalization and aggregation assay in HEK293T cells, we identified posaconazole, an FDA-approved, CNS-penetrant and orally delivered anti-fungal, as the strongest inhibitor of TDP-43 pathology. Posaconazole was able to reduce insoluble TDP-43 and restore SREBP2 levels, outperforming ketoconazole. Mechanism of action (MOA) experiments suggest posaconazole is able to outperform ketoconazole by inducing a significantly stronger activation of autophagy and upregulation of heat shock proteins known to clear TDP-43. Further MOA experiments show that the effects of posaconazole on TDP-43 are dependent on its known ability to lower cellular cholesterol levels. By correlating our experimental results on the eight CYP51 inhibitors tested, we show that predicted affinity towards human CYP51 strongly correlates with the inhibitors' ability to lower TDP-43 aggregation and mislocalization. Finally, we tested posaconazole in a low dose sodium arsenite ALS model in iPSC-derived motor neurons, showing that it is efficacious at inhibiting TDP-43 pathology in the nanomolar range. Altogether, these results support the repurposing of posaconazole for ALS/FTD as a means to prevent TDP-43 pathology.

DOI: https://doi.org/10.64898/2026.06.01.728552
bioRxiv. 2026 Jun 03. pii: 2026.05.30.729013. [Epub ahead of print]

PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model.

Issa O Yusuf, Rogerio L A Silva, George G Amoako, Paul R Thompson, Zuoshang Xu.

Background: Dysregulated peptidyl deiminase 2 (PAD2) and aberrant protein citrullination (PC), a posttranslational modification (PTM), are involved in various inflammatory and neurodegenerative diseases. We previously showed in transgenic mice and postmortem human tissues that PC and PAD2 are altered in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons loss, paralysis, and death. Herein, we investigated the role of PAD2 in ALS by PAD2 knockout in a SOD1-ALS mouse model.
Methods: To investigate the role of PAD2-induced citrullination in ALS pathogenesis, we generated PAD2 knockout (PAD2KO) in SOD1 G93A ALS mouse model and investigated the consequent modulation on the neuropathology and clinical symptoms, using molecular biology techniques such as qPCR, Western blotting, confocal microscopy, and electron microscopy. Additionally, we identified C3 as being citrullinated in human ALS using ionFinder.
Results: Our results show that PAD2KO blocked the increased PC and reduced myelin basic protein (MBP) aggregates in the ALS model. PAD2KO also improved motor neuron survival and the integrity of myelin, axons, and neuromuscular junctions, and reduced microgliosis in the white matter and C3 protein levels in astrocytes. Clinically, data from monitoring the body weight changes suggests that PAD2KO modulates the course of the disease in the ALS mouse model, accelerating the onset while slowing the progression after the onset, and modestly extending the survival of male mice.
Conclusion: These results show that PAD2 is responsible for the increased PC in ALS and PC contributes to neuroinflammation and degeneration of motor neurons and myelinated axons. The modest modulation of the disease phenotype suggests that the role of PC in ALS is complex, involving altered PC in numerous proteins and in multiple cell types. Future studies are needed to investigate how PC modulates individual protein functions in various cell types to understand the contribution of PC to ALS pathogenesis.

DOI: https://doi.org/10.64898/2026.05.30.729013
Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00615-7. [Epub ahead of print]45(6): 117537

Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.

Ruoxi Wang, Tina M Fortier, Xiaofeng Sun, Fei Chai, Panagiotis D Velentzas, Eric H Baehrecke.

  Selective removal of endoplasmic reticulum (ER) is important for cell health. Macroautophagy is the primary mechanism for the removal of the ER, but the ER can be cleared in a macroautophagy-independent manner. However, the physiological relevance and mechanisms underlying macroautophagy-independent ER clearance remain largely unknown. Here we show that ER is cleared by lysosomes in a macroautophagy Atg gene-independent manner during development. This developmentally programmed Atg-independent ER clearance by lysosomes requires the ER protein Vap33 that promotes ER and lysosome contact. Oxysterol-binding protein (Osbp) is known to associate with Vap33, and Osbp lysosomal localization is required for ER clearance in cells lacking macroautophagy. Significantly, the cholesterol transport-associated protein Start1 regulates ER and lysosome contact, macroautophagy-independent ER clearance, and cholesterol transport from ER to the lysosome. These studies reveal that Vap33, Osbp, and Start1 promote ER clearance by lysosomes that is associated with cholesterol trafficking.

Keywords:  CP: cell biology; Drosophila; ER; ESCRT; Osbp; Start1; Vap33; lysosome

DOI:  https://doi.org/10.1016/j.celrep.2026.117537
J Neurochem. 2026 Jun;170(6): e70495

Septins in the Middle-Makers and Breakers of Membrane Contact Sites.

TrishaJean J Holt, Elias T Spiliotis.

Intracellular communication in neurons requires precise coordination of signals across geometrically complex and highly compartmentalized cellular architectures. Membrane contact sites (MCS)-specialized junctions where two organelles are closely apposed without undergoing fusion-have emerged as key organizational hubs enabling efficient exchange of ions, lipids, and metabolites, yet the cytoskeletal proteins that organize and regulate these junctions remain poorly understood. Here, we review evidence that septins-a conserved family of heteromeric GTP-binding proteins that assemble into filamentous oligomers and polymers-function as integral components of MCS in neurons and beyond. Septins associate with hyperboloid, hourglass-shaped membrane curvatures and distinct membrane domains and organelles through polybasic motifs, amphipathic helices, and transmembrane domains. We review how septins establish diffusion barriers at endoplasmic reticulum (ER)-plasma membrane (PM) contacts in budding yeast and consider evidence that analogous mechanisms operate at dendritic branch points and spine necks in mammalian neurons. We examine septin roles in regulating store-operated calcium entry at ER-PM contacts and explore how septins regulate membrane contacts at presynaptic active zones. Additionally, we highlight how septins organize membrane contacts between host organelles and intracellular pathogens, scaffolding autophagic, mitochondrial, and lysosomal membranes for bacterial clearance. Collectively, these findings support the view that septins constitute a versatile and underappreciated class of MCS tethers whose paralog- and isoform-specific complex compositions may confer spatial and functional selectivity for distinct MCS, opening new avenues for understanding organelle connectivity in health and disease.

DOI: https://doi.org/10.1111/jnc.70495
bioRxiv. 2026 Jun 03. pii: 2026.05.31.729085. [Epub ahead of print]

The structural basis for LRRK2's activation and autoinhibition.

Amalia Villagran Suarez, Kathryn S Hatch, Tatyana Bodrug, Wei Gai, Katherine J Surridge, Elizabeth Moussikhina, Kendrick Hv Nguyen, Marta Sanz-Murillo, Robert Callahan, Erica Xiong, Delisa Ramos, Lawrence Zhu, Verena Dederer, Sebastian Mathea, Janet Iwasa, Stefan Knapp, Kevan M Shokat, Samara L Reck-Peterson, Andres E Leschziner.

Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-EM, biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the GDP-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.

DOI: https://doi.org/10.64898/2026.05.31.729085
Brain. 2026 Jun 08. pii: awag202. [Epub ahead of print]

Restoring DSCAM expression mitigates neuronal morphology and axon guidance deficits in Down syndrome.

Manasi Agrawal, Nikita Kirkise, Katelyn Rygel, Pabitra K Sahoo, Carly J Vincent, Daniel Joyner, Ricardo Aguilar-Alvarez, Trey R Philipp, Parker S Dhillon, Juhi Patel, Jeffery Twiss, Aaron M Jasnow, Kristy Welshhans.

  Down syndrome results from the triplication of human chromosome 21 and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on human chromosome 21 and is overproduced in Down syndrome. DSCAM is a homophilic cell adhesion molecule, a receptor for netrin-1, and plays a critical role in neural wiring during brain development. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell-derived cortical neurons, in combination with cellular, molecular, and behavioral approaches, this study aims to understand how DSCAM triplication and its subsequent excessive production contribute to changes in neural development and intellectual disability in Down syndrome. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. DSCAM overexpression also reduces interhemispheric connectivity in vivo. Furthermore, we find that DSCAM overexpression leads to impaired hippocampal-dependent learning and reduced anxiety in adult mice. Down syndrome human induced pluripotent stem cell-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in Down syndrome human induced pluripotent stem cell-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. This study presents the first comprehensive cellular, molecular, and behavioural evidence that DSCAM is a significant contributor to multiple Down syndrome phenotypes, providing insight into a pathway for treatment. In summary, these results suggest that DSCAM plays an essential role in the development of neurons and neuronal networks, and its overproduction contributes to intellectual disability in Down syndrome.

Keywords:  DSCAM; Down syndrome; axon guidance; intellectual disability; memory; neuron morphology

DOI:  https://doi.org/10.1093/brain/awag202
Curr Neuropharmacol. 2026 Jun 08.

The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?

Ekta Shirbhate, Vaibhav Singh, Om Kumar Mishra, Biplob Koch, Amit K Tiwari, Haya Khader Ahmad Yasin, Harish Rajak.

  The review specifically examines the pivotal role of HDAC6 in the pathophysiological pathway of Amyotrophic Lateral Sclerosis (ALS), an escalating neurodegenerative ailment marked by the discerning damage to motor neurons. Several lines of evidence implicate inadequate proteostasis in significantly influencing neuronal degeneration. The accumulation of misfolded proteins and proteotoxicity are highlighted as significant factors in ALS pathophysiology. Key pathological hallmarks include ubiquitin-positive inclusions, disrupted RNA metabolism, cytoskeletal perturbations, and compromised axonal transport systems. HDAC6 dysregulation disrupts axonal transport, impairing mitochondrial function and increasing oxidative stress, leading to rapid motor neuron damage and cell death. The enzyme's aberrant deacetylation of α-tubulin destabilizes microtubules and impairs intracellular trafficking. Despite HDAC6's participation in these unfavorable processes, it also exerts neuroprotective properties. It deacetylates tubulin, promoting efficient axonal transport and autophagic clearance. HDAC6 helps form aggresomes and stress granules, which are essential for cellular defence against proteotoxic stress. Through its zinc finger ubiquitin-binding domain, HDAC6 interacts with polyubiquitinated proteins, facilitating their autophagic degradation. HDAC6 inhibition can boost autophagic flux and reduce protein aggregation, while its activation may amplify the protective effects. This dichotomous behaviour of HDAC6 may pose an obstacle to the design of targeted therapy. Illuminating the complex mechanisms through which HDAC6 influences neurodegeneration and neuroprotection is important before constructing effective treatments for ALS. The review provides a clear understanding of the complex role of HDAC6 in ALS pathogenesis and highlights potential strategies to improve the prognosis of people affected by this neurological illness.

Keywords:  ALS; FUS; HDAC6; HDAC6 inhibitors; de-acetylation; neurodegenerative diseases.

DOI:  https://doi.org/10.2174/011570159X462214260429080002
Curr Neuropharmacol. 2026 Jun 08.

Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.

Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.

Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.

DOI:  https://doi.org/10.2174/011570159X473929260605103158
J Cell Sci. 2026 Jun 08. pii: jcs.264795. [Epub ahead of print]

Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.

Ranran Mao, Jiaqi Zhai, Chunfang Tong, Wenfeng Fu, Dong Li, Jia-Jia Liu.

  In eukaryotic cells, organelles communicate through membrane contact sites-specialized regions where their membranes come into close apposition without fusing. Among these, contacts between the endoplasmic reticulum (ER) and the Golgi apparatus are critical for lipid trafficking and polarized sorting of protein cargoes, yet their regulation and physiological roles remain poorly understood due to limited research tools. Here, we developed genetically encoded biosensors that selectively label ER-Golgi contact sites by building upon split GFP/YFP systems. These fluorescent probes reliably detect ER-Golgi contacts whose formation depends on Golgi-enriched phosphatidylinositol 4-phosphate and the lipid transfer activity of Oxysterol-Binding Protein, and reveal the dynamic remodeling of these structures in live cells. Notably, the biosensors captured alterations in ER-Golgi contacts during cell division and ER stress, as well as their developmental loss in mammalian neurons. We propose these biosensors as powerful tools for investigating ER-Golgi interactions in response to physiological cues or pathological perturbations across diverse cell types.

Keywords:  Biosensor; Endoplasmic reticulum; Golgi; Membrane contact sites; Split GFP

DOI:  https://doi.org/10.1242/jcs.264795
Tissue Cell. 2026 Jun 10. pii: S0040-8166(26)00386-1. [Epub ahead of print]103 103692

VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.

Rabab S Hamad, Eman Hamza, Ebtehal M Abdel-Aal, Elsayed A Elmorsy, Hanan Eissa, Alshaimaa A Farrag, Ahmed Shata, Ghada M Nassar, Nesreen Elsayed Morsy, Ahmed A El-Mansy, Ahmed G Hamad, Eman R Abdellatif, Sameh Saber.

  Organelle contact sites are increasingly recognized as regulatory interfaces that coordinate lipid transfer, ion signaling, and metabolic adaptation. In neurons, communication among the endoplasmic reticulum (ER), lysosomes, and mitochondria is essential for cellular homeostasis. Recent studies have identified vacuolar protein sorting 13 homolog C (VPS13C), a lipid transport protein, as a key mediator of ER-lysosome tethering and as an important component of the response to lysosomal stress. Structural analyses show that VPS13 family proteins form elongated lipid transport channels that are proposed to facilitate phospholipid transfer between adjacent membranes. Following lysosomal damage, VPS13C is recruited to ER-lysosome contact interfaces, where it forms tethering bridges that may support membrane repair by enabling high-capacity lipid transfer from the ER to lysosomal membranes. Beyond membrane repair, these contact interfaces may also participate in broader organelle communication networks. ER-lysosome contacts can occur in proximity to ER-mitochondria junctions, potentially forming multi organelle signaling hubs that coordinate lipid redistribution, calcium signaling, and mitochondrial adaptation. These signals may influence downstream responses, including activation of TFEB and TFE3, which regulate lysosomal biogenesis and autophagy. Disruption of this contact site network has emerged as a potential contributor to Parkinson's disease. Loss of VPS13C function is associated with altered lysosomal homeostasis and intersects with pathogenic pathways involving α-synuclein aggregation, PINK1/Parkin-mediated mitophagy, and LRRK2 signaling. This review presents a framework in which ER-lysosome tethering is considered part of a staged cellular damage response linking membrane repair, metabolic coordination, and transcriptional adaptation.

Keywords:  ER-lysosome tethering; Lipid transfer; Lysosomal membrane repair; Organelle contact sites; Parkinson’s disease; VPS13C

DOI:  https://doi.org/10.1016/j.tice.2026.103692
J Neurochem. 2026 Jun;170(6): e70493

Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on TDP-43 Proteinopathy.

Serena Scozzari, Stefano Fabrizio Columbro, Monica Favagrossa, Massimo Tortarolo, Alfredo Cagnotto, Mario Salmona, Giovanni De Marco, Caterina Bendotti, Andrea Calvo, Laura Pasetto, Valentina Bonetto.

  Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isomerase A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA Lys-acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP-43 proteinopathy in vitro and in vivo and how this relates with PPIA. We found that vorinostat/SAHA, a broad-spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP-43 mislocalization in a cellular model of TDP-43 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP-43 proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co-inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP-43 accumulation in the sciatic nerve and acetylcholine receptor γ-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP-43 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of lysine deacetylation inhibition and arimoclomol shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.

Keywords:  HDAC inhibitors; Lys‐acetylation; TDP‐43 proteinopathy; arimoclomol; peptidyl‐prolyl cis‐trans isomerase a

DOI:  https://doi.org/10.1111/jnc.70493
bioRxiv. 2026 Jun 01. pii: 2026.05.28.728543. [Epub ahead of print]

Morphology-robust quantification of subcellular organization in complex cells.

Robert Hu, Nima N Naseri, Ophir Shalem, Pablo G Camara.

Quantitative analysis of subcellular protein organization is often confounded by variation in cell morphology, limiting the identification and interpretation of localization patterns in fluorescence microscopy data from morphologically complex cells, such as neurons and glia. We introduce CellAligner, an unsupervised framework that uses fused unbalanced Gromov-Wasserstein couplings to map protein distributions from morphologically distinct cells into shared anchor-cell geometries, enabling morphology-robust comparison of subcellular localization. In neuronal imaging benchmarks, applying current image-analysis methods (CellProfiler, Cytoself, Paired Cell Inpainting) to CellAligner's anchor-cell representations substantially reduced morphology-associated confounding while approximately doubling their multiclass MCC for localization classification. We demonstrate its biological utility by identifying U18666A-induced lysosomal trafficking defects in human iPSC-derived neurons. To scale the approach, we developed dCellAligner-OT, a fast deep metric learning model that approximates CellAligner's optimal transport distances and anchor-cell representations, enabling atlas-scale analyses. CellAligner provides a general framework for morphology-robust analysis of subcellular organization in complex cellular systems.

DOI: https://doi.org/10.64898/2026.05.28.728543
Neurosci Res. 2026 Jun 11. pii: S0168-0102(26)00067-2. [Epub ahead of print] 105080

Enhanced Calcium Activity and Transcriptomic Alterations in iPSC-derived Neurons from BAFME Patients with Repeat Expansions.

Yuki Nagasako, Mitsuru Ishikawa, Hiroyuki Ishiura, Sopak Supakul, Sumihiro Maeda, Tatsushi Toda, Shoji Tsuji, Hideyuki Okano.

  Benign adult familial myoclonus epilepsy (BAFME) is caused by intronic TTTCA and TTTTA repeat expansions in SAMD12 and other genes; the neuronal basis of cortical hyperexcitability, however, remains unclear. We generated induced pluripotent stem cell (iPSC)-derived glutamatergic and GABAergic neurons from three BAFME1 patients and examined functional and transcriptomic phenotypes. Patient-derived neurons retained the pathogenic repeat expansions and showed a tendency toward upstream intronic RNA accumulation. Calcium imaging revealed increased spontaneous Ca2+ transient frequency in both neuronal subtypes, indicating heightened activity. Pharmacological profiling demonstrated attenuated responses to calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (CP-AMPAR) blockade and GABAA receptor antagonism in GABAergic neurons, suggesting altered inhibitory signaling. RNA sequencing revealed transcriptomic alterations without differential expression of ion channels and neurotransmitter receptors. In glutamatergic neurons, ATF4-regulated genes, including SLC7A5 encoding LAT1, a Kv1.2 channel modulator, were downregulated. Reduced SLC7A5 expression was validated at both mRNA and protein levels. In GABAergic neurons, synapse-associated genes PTPRD and GPC6 were upregulated. TCERG1L and NLRP2 were suppressed across both neuronal subtypes. These findings suggest subtype-specific alterations may contribute to neuronal hyperexcitability in BAFME and provide a platform for mechanistic studies of repeat expansion-associated epilepsies.

Keywords:  BAFME; GABAergic neurons; Induced pluripotent stem cells; calcium imaging; epilepsy; glutamatergic neurons; repeat expansion

DOI:  https://doi.org/10.1016/j.neures.2026.105080
Neurobiol Dis. 2026 Jun 09. pii: S0969-9961(26)00222-6. [Epub ahead of print]227 107477

Loss of astrocytic markers and impaired metabolic function in spinocerebellar ataxia type 7 patient-derived neural cultures.

Linde F Bouwman, Ronald A M Buijsen, Linda M van der Graaf, Barry A Pepers, Bas J B Voesenek, Hailiang Mei, Bart P C van de Warrenburg, Willeke M C van Roon-Mom.

  Spinocerebellar ataxia type 7 (SCA7) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the ATXN7 gene. This repeat expansion results in an abnormally long polyglutamine (PolyQ) tract in the Ataxin-7 protein. This ultimately leads to the degeneration of most notably Purkinje cells and retinal cells. Because no treatment exist that can halt or slow disease progression, there is a critical need for patient-specific disease models to uncover new pathogenic mechanisms and enable therapeutic testing. In this study, induced human pluripotent stem cells (hiPSCs) derived from healthy controls and individuals with SCA7 were differentiated into a mixed neural cell population consisting of neurons and astrocytes. Although control and SCA7 neurons appeared morphologically similar, SCA7-derived astrocytes exhibited a pronounced loss of the astrocyte-specific markers GFAP and S100B. Transcriptome analysis revealed substantial alterations in genes related to glial differentiation, cellular metabolism and oxygen handling, protein homeostasis, and neuronal differentiation and neuronal signalling. Mitochondrial stress assays further confirmed a mitochondrial phenotype in SCA7 neural cells. Together, these findings demonstrate that hiPSC-derived neural cells provide a robust platform that can be used for studying disease mechanisms and testing potential therapies for SCA7.

Keywords:  Astrocytes; Disease modeling; Human induced pluripotent stem cell-derived neural cultures; Metabolic profiling; Neurodegeneration; Neurons; Spinocerebellar ataxia type 7; Transcriptome analysis

DOI:  https://doi.org/10.1016/j.nbd.2026.107477
Mol Neurobiol. 2026 Jun 10. pii: 685. [Epub ahead of print]63(1):

Mitochondrial Dysfunction as a Driver of Neurodegeneration in Parkinson's and Huntington's Disease: Molecular Insights and Emerging Interventions.

Omkar Kumar Kuwar, Sarila Khan, Ayushi Maloo, Chetna Singh, Mansi Sharma, Kousik Maparu, Mamta Sachdeva Dhingra, Vipul Sharma.

  Mitochondrial dysfunction has emerged as a central contributor to the pathogenesis of major neurodegenerative disorders, such as Parkinson's and Huntington's disease. In Parkinson's disease, mitochondrial abnormalities are often linked to mutations in genes like PINK1 and Parkin, which regulate mitochondrial quality control, while α-synuclein aggregation further exacerbates mitochondrial damage. In Huntington's disease, mutant huntingtin protein impairs mitochondrial dynamics, transport, and ATP production, contributing to selective neuronal vulnerability. The convergence of mitochondrial impairments across both diseases highlights a common pathological axis that can be therapeutically targeted. This review critically examines the molecular underpinnings of mitochondrial dysfunction in PD and HD and explores emerging strategies to restore mitochondrial function. These include antioxidants, metabolic modulators, mitophagy activators, and gene therapy approaches. Despite promising preclinical findings, several translational challenges remain, underscoring the need for continued investigation. Understanding the shared and unique mitochondrial-related mechanisms in PD and HD will be essential for developing targeted, disease-modifying therapies that may improve outcomes and quality of life for affected individuals.

Keywords:  Antioxidants; Huntington’s disease; Mitochondrial dysfunction; Neuroinflammation; Neuronal loss; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-026-05991-w
JCI Insight. 2026 Jun 11. pii: e198842. [Epub ahead of print]

Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.

Daisuke Ito, Madoka Iida, Yohei Iguchi, Atsushi Hashizume, Shinichiro Yamada, Yoshiyuki Kishimoto, Shota Komori, Kazuki Obara, Shuto Nishisaki, Satoshi Yokoi, Teppei Shimamura, Yuto Takemoto, Masahiro Nakatochi, Tomohiro Akashi, Kunihiko Hinohara, Hyeon-Cheol Lee-Okada, Yohei Okada, Junichi Niwa, Gen Sobue, Shinji Tanaka, Ken Takashina, Takehiko Yokomizo, Masahisa Katsuno.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.

Keywords:  ALS; Biomarkers; Drug therapy; Metabolism; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.198842
bioRxiv. 2026 Jun 02. pii: 2026.05.29.728874. [Epub ahead of print]

α-Synuclein and γ-Tubulin Cooperatively Regulate Activity-Evoked Presynaptic Microtubule Nucleation to Gate Dopamine Release.

Alessandro Comincini, Sejoon Choi, Eugene V Mosharov, Edoardo Milanetti, Ellen Kanter, Giancarlo Ruocco, Graziella Cappelletti, David Sulzer, Francesca Bartolini.

α-Synuclein has long been implicated in the regulation of synaptic activity, but the molecular basis that underlies this function has been elusive. Here, we identify a microtubule (MT)-dependent mechanism through which α-synuclein regulates synaptic dopamine release. Using live imaging of cultured dopaminergic neurons, we visualize dynamic MTs at individual presynaptic boutons and show that neuronal activity triggers local γ-tubulin-dependent MT nucleation. We find that this nucleation is essential for interbouton synaptic vesicle (SV) transport and for sustained dopamine release during high activity. We further discover that α-synuclein acts as a positive regulator of presynaptic MT nucleation by binding directly to γ-tubulin and the α/β-tubulin heterodimer. Activity-evoked phosphorylation of α-synuclein at serine 129, a modification that accumulates in synucleinopathies and a molecular switch for α-synuclein binding to synaptic proteins, occurs in the region of α/m tubulin binding and is both necessary and sufficient for MT initiation. Our findings reveal a previously unrecognized, activity-dependent role for α-synuclein in the nucleation of axonal MTs that enables on-demand SV interbouton redistribution and dopamine release. This mechanism provides a novel molecular link between α-synuclein phosphorylation and MT-dependent modulation of dopamine release, offering insight into how its dysregulation may contribute to dopaminergic synaptic dysfunction, a central feature of synucleinopathies.

DOI: https://doi.org/10.64898/2026.05.29.728874
Res Sq. 2026 Jun 01. pii: rs.3.rs-9853460. [Epub ahead of print]

Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes.

Johnathan Cooper-Knock, Sam Bonsall, Rodrigo Kazu, Marianne King, Diana Leung, Farah Mahiddine, J Highley, Andrew Strange, Yongzhuo Chen, Matilde Sassani, Mahmoud Eldahshoury, James Boyne, Mark Collins, Emma Monte, Calum Harvey, Sarah Gornall, Akanksha Jangid, Connie Treanor, Tobias Moll, Charlotte van Dijk, Sara Cabras, Alexander Urban, Katie Bowden, Hollie Wareing, Yiling Huang, Pamela Shaw, Ryan West, Kevin Kenna, Eran Hornstein, Sai Zhang, Jingtian Zhou, Michael Snyder.

Amyotrophic lateral sclerosis (ALS) causes selective neurodegeneration in primary motor cortex, yet cell-type-specific molecular changes driving this vulnerability remain poorly understood. We present an integrated single-nucleus RNA- and ATAC-sequencing atlas of 778,330 nuclei from the primary motor cortex of 140 genetically characterised donors. ALS is associated with widespread transcriptional reprogramming driven by a common set of transcription factors (TFs) across multiple cell-types. Astrocytes harbour the most differentially expressed genes. Within astrocytes, a WDR49-expressing subpopulation is spatially associated with TDP-43 pathology, and genetic variants within WDR49 confer risk for both sporadic and monogenic autosomal dominant ALS. In patient-derived induced astrocytes, WDR49 protein abundance predicts the survival of co-cultured neurons. WDR49 localises to PML nuclear bodies, where it regulates astrocyte reactivity and secretion of EVs containing protein chaperones. Together, these in vivo and in vitro findings suggest that WDR49+ astrocytes mount a compensatory secretory response to extracellular protein aggregates, and that loss of this capacity lowers the threshold for ALS pathogenesis.

DOI: https://doi.org/10.21203/rs.3.rs-9853460/v1
Brain. 2026 Jun 10. pii: awag185. [Epub ahead of print]

Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse.

Ilaria Donati Della Lunga, Letizia Cerutti, Valerio Barabino, Gioele G Figus, Francesca Callegari, Luca Oneto, Mariateresa Tedesco, Francesca Bacchetti, Marco Milanese, Paolo Massobrio, Martina Brofiga.

  Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved. In this study, we reconstruct the developmental trajectory of cultured cortical networks derived from SOD1G93A mouse embryos using a multimodal approach, by combining morphometric, electrophysiological, pharmacological, molecular, computational, and machine-learning techniques. We prove that ALS neurons fail to acquire mature polarization and connectivity, displaying a transient phase of hyperexcitability that precedes a progressive collapse of network organization. Astrocytic dysfunction emerges early and impairs synchronization, establishing a causal link between glial dysfunction and neuronal instability. The analysis of synaptic transmission reveals an excitatory bias followed by maladaptive inhibitory recruitment and GABA/glutamate co-release, causing fragmented and inefficient network topologies. Finally, in silico modelling identified deficient intrinsic adaptation as a key driver of hyperexcitability. Together, our findings position ALS as a developmentally rooted disorder of cultured cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures. By demonstrating that cortical dysfunction is embedded before degeneration, this work provides a unifying framework connecting early network instability to disease progression and establishes electrophysiological network signatures, detected by machine learning classifiers, as candidate biomarkers for early diagnosis and therapeutic screening.

Keywords:  ALS; astrocyte dysfunction; electrophysiology; excitatory/inhibitory imbalance; in silico modeling; machine learning

DOI:  https://doi.org/10.1093/brain/awag185
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2520331123

Dysregulation of autophagosome-mitochondria contacts contributes to autophagy dysfunction and neurodegeneration in tauopathy.

Nuo Jia, Hongyuan Guan, Yantao Zuo, Yu Young Jeong, Niharika Amireddy, Gavesh Rajapaksha, Cuauhtemoc Ulises Gonzalez, Nora Jaber, Yun-Kyung Lee, Marialaina Nissenbaum, David J Margolis, Wei Dai, Alexander W Kusnecov, Qian Cai.

  Mitochondria (Mito) engage in extensive communication with other organelles through membrane contacts. Perturbed mitochondria-organelle interactions are indicated in a variety of neurodegenerative diseases, but the underlying mechanisms remain poorly understood. Here, we report a class of mitochondria-organelle communication: autophagosome/autophagic vacuole (AV)-Mito contact, which exhibits hypertethering in tauopathy neurons, consequently hampering AV retrograde transport. Such defects are attributed to accelerated turnover of the contact release factor TBC1D15, triggered by mitochondrial bioenergetic deficit-induced hyperactivity of the adenosine monophosphate-activated protein kinase (AMPK). Increasing TBC1D15 levels or repressing AMPK activity normalizes AV-Mito contact release and restores retrograde transport of AVs, thereby increasing autophagic cargo clearance and reducing tau burden in tauopathy axons. Furthermore, overexpression of TBC1D15 enhances autophagic clearance and attenuates tau pathology, alleviating neurodegeneration and cognitive dysfunction in tauopathy mice. Taken together, our study provides mechanistic insights into AV-Mito contact dysregulation in tauopathy-related autophagy failure, laying the groundwork for the development of potential therapeutics to combat tauopathy diseases.

Keywords:  autophagosome retrograde transport; autophagosome–mitochondria contact; autophagy; mitochondrial bioenergetics; tauopathy

DOI:  https://doi.org/10.1073/pnas.2520331123
Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00167-0. [Epub ahead of print] 102956

Suppression of ATM kinase signaling accelerates cellular senescence.

Kei-Ichi Ishikawa, Takahiro Shiga, Takumi Hirose, Naoko Kuzumaki, Sakura Miyoshi, Akihiro Yamaguchi, Hidetaka Tamune, Avijite Kumer Sarkar, Kento Nakai, Kazuyoshi Baba, Shigeo Okabe, Nobutaka Hattori, Hideyuki Okano, Wado Akamatsu.

  Cells derived from rejuvenated human induced pluripotent stem cells (hiPSCs) require extended culture periods to achieve functional maturation, and it remains difficult to recapitulate cellular senescence in these cells in vitro. This limitation hinders the accurate and efficient modeling of age-related neurodegenerative diseases. Here, we aimed to establish a simple approach to promote neuronal maturation and improve the efficiency of hiPSC-based disease modeling. Using a small-molecule inhibitor library, we identified an ATM kinase inhibitor, KU60019, that promotes both maturation-associated features and senescence-associated phenotypes in hiPSC-derived neurons and fibroblasts. KU60019 treatment promoted the manifestation of disease-relevant phenotypes in hiPSC models of age-related neurodegenerative diseases. Furthermore, senolytic analyses suggested that KU60019-induced senescent cells depend on pro-survival pathways, including HSP90-associated signaling. These findings suggest that KU60019 provides a simple and useful tool for accelerating phenotypic recapitulation in hiPSC models of age-related neurodegenerative diseases.

Keywords:  ATM kinase; Alzheimer’s disease; KU60019; Parkinson’s disease; cellular senescence; human induced pluripotent stem cells; neurodegenerative disease modeling; neuronal maturation

DOI:  https://doi.org/10.1016/j.stemcr.2026.102956
Sci Adv. 2026 Jun 12. 12(24): eaee9856

Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.

Shuliang Chen, Subhrajit Banerjee, Dongmei Liu, Kamal Kumar, Christopher J Obara, Peter Novick, William A Prinz, Susan Ferro-Novick.

During cell stress, endoplasmic reticulum autophagy (ER-phagy) receptors remodel the ER by sequestering membrane proteins (cargo) into autophagosomes for degradation. The conserved ER-phagy receptor, Atg40, contains a motif that binds to Atg8 and a reticulon homology domain that is needed for vacuolar/lysosomal delivery. Cargo capture, however, requires the Atg40 binding partner Lst1/SEC24C. To address whether lipids regulate cargo capture during ER-phagy, we analyzed autophagy in neutral lipid-deficient cells. Unexpectedly, we found that Atg40 was delivered to the vacuole in autophagosomes without Lst1/SEC24C or cargo in mutant cells. Lipidomic analysis revealed changes in the ratio of phosphatidylethanolamine to phosphatidylcholine in the neutral lipid-deficient cells that are predicted to alter ER membrane bendability. Our findings imply that phospholipids control cargo sequestration by regulating receptor-cargo coupling at autophagic sites.

DOI: https://doi.org/10.1126/sciadv.aee9856
Nat Commun. 2026 Jun 12.

Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.

Angelica E Lang, Chris Stein, Roger Schultz, Catherine M Drerup.

To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a significant portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.

DOI: https://doi.org/10.1038/s41467-026-74127-4
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00078-6. [Epub ahead of print]208 99-114

Quantification of cell viability by automated analysis of live cell imaging.

Jan C d'Engelbronner, Stefanie Rufli, W Wei-Lynn Wong.

  Accurate assessment of cell viability is fundamental in biomedical research, with applications ranging from cancer biology to drug discovery. Traditional assays based on metabolic activity or membrane integrity are cost-effective but limited to endpoint measurements, often overlooking the dynamic nature of cell survival and death. Here, we present a workflow that combines live cell imaging with automated image analysis to provide continuous, unbiased quantification of cell viability. Using a fluorescent marker of membrane integrity and nuclear staining, time-lapse microscopy captures cell fate dynamics under diverse experimental conditions. Automated segmentation and classification, implemented through the open-source DIPlib library, enable reproducible distinction between viable and non-viable cells while minimizing observer bias. The method is scalable, adaptable to different imaging platforms and suitable for high-throughput applications.

Keywords:  automated image analysis; cell viability quantification; live cell imaging; single cell analysis

DOI:  https://doi.org/10.1016/bs.mcb.2026.02.010