bims-axbals 2026-04-12 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–04–12
nineteen papers selected by
TJ Krzystek

Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.
Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.
PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.
Microtubules in the axon are GDP bound but adopt a stable GTP-like expanded state.
Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks.
CNS-compartmentalized IgG aggregates and glycosylation in multiple sclerosis contribute to oligoclonal bands and neuronal cytotoxicity.
Aberrant FICD-mediated AMPylation drives α-Synuclein pathology and overall protein dyshomeostasis in dopaminergic neurons in Parkinson's disease.
Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.
Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.
Tracking tau and cellular responses in human iPSC-microglia: from uptake to seedable secretion, including in extracellular vesicles.
A human iPSC model of tauopathies engineered for 4R tau isoform expression endogenously develops late-stage neuronal tau pathology.
Single transient exposure to low-frequency low-intensity electrical stimulation produces ketamine-like effects in human iPSC-derived dopaminergic neurons via Ca2+-dependent BDNF and mTOR signaling.
Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
The SWR1 complex prevents the vacuolar delivery of ATG proteins through a noncanonical pathway.
Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
The dynamics of centromere assembly and disassembly during quiescence.
Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.
Wild-type huntingtin in neurodevelopment.
Mitochondrial Transfer: From Bench to Bedside.

PLoS One. 2026 ;21(4): e0346613

Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.

Alexandre Emond, Carl Laflamme, Martine Therrien, Meijiang Liao, Claudia Maios, Audrey Labarre, Pierre Drapeau, J Alex Parker.

Intronic hexanucleotide repeat expansions in the C9orf72 gene represent the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This expansion decreases C9orf72 expression in affected patients, indicating that loss of C9orf72 function (LOF) acts as a pathogenic mechanism. Several models using Danio rerio (zebrafish) for C9orf72 depletion have been developed to explore disease mechanisms and the consequences of C9orf72 LOF. However, inconsistencies exist in reported phenotypes, and many have yet to be validated in stable germline ablation models. To address this, we created a zebrafish C9orf72 knockout model using CRISPR/Cas9. The C9orf72 LOF model demonstrates, in a generally dose-dependent manner, increased larval mortality, persistent growth reduction, and motor deficits. Additionally, homozygous C9orf72 LOF larvae exhibited mild overbranching of spinal motoneurons. To identify potential therapeutic compounds, we performed a screen on an established Caenorhabditis elegans (C. elegans) C9orf72 homologue (alfa-1) LOF model, identifying 12 compounds that enhanced motility, reduced neurodegeneration, and alleviated paralysis phenotypes. Motivated by the shared motor phenotype, 2 of those compounds were tested in our zebrafish C9orf72 LOF model. Pizotifen malate was found to significantly improve motor deficits in C9orf72 LOF zebrafish larvae. We introduce a novel zebrafish C9orf72 knockout model that exhibits phenotypic differences from depletion models, providing a valuable tool for in vivo C9orf72 research and ALS therapeutic validation. Furthermore, we identify pizotifen malate as a promising compound for further preclinical evaluation.

DOI: https://doi.org/10.1371/journal.pone.0346613
Brain Commun. 2026 ;8(2): fcag104

Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.

Olivia M Rifai, Fergal M Waldron, Judi O'Shaughnessy, Fiona L Read, Martina Gilodi, Annalisa Pastore, Neil A Shneider, Gian Gaetano Tartaglia, Elsa Zacco, Holly Spence, Jenna M Gregory.

  Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALS-FTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43. Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion (12/30) of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS). Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell-type predominance and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43APT), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron. Intra-neuronal pTDP-43 and cytoplasmic TDP-43APT pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43APT staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43APT pathology, representing a potential region-specific imaging biomarker (e.g. volumetric or susceptibility-weighted MR imaging) of early disease in ALS.

Keywords:  ALS; ECAS; TDP-43; behaviour; cognition

DOI:  https://doi.org/10.1093/braincomms/fcag104
J Cell Biol. 2026 Jun 01. pii: e202508040. [Epub ahead of print]225(6):

PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.

Shan Zhao, Jie Zhang, Tengfei Ma, Jinglin Li, Mei Duan, Xin Wang, Meijiao Li, Chonglin Yang.

Mitochondria form highly complex and dynamic networks to maintain their homeostasis. However, the underlying mechanisms remain elusive. Here we report a PI(3)P-dependent mechanism that regulates the mitochondrial dynamics required for formation of mitochondrial networks. Using genetic screening, we reveal that mutations of Caenorhabditis elegans EXC-5/FGD lead to formation of spherical and unconnected mitochondria. EXC-5 binds to endosomal PI(3)P generated by the PI 3-kinase VPS-34 and is recruited to endosome-mitochondrion contacts, where it acts as the guanine nucleotide exchange factor to activate the CDC-42 GTPase. Loss of exc-5 or vps-34 similarly disrupts mitochondrial and actin networks as well as mitochondrial recruitment of DRP-1, leading to failure of mitochondrial fission, branching, and elongation. In contrast, expression of constitutively activated CDC-42 ameliorates the defective mitochondrial networks in an actin-dependent manner. Together, these findings suggest a PI(3)P-EXC-5-CDC-42 axis that acts at endosome-mitochondrion contacts to regulate actin organization for maintenance of mitochondrial dynamics and networks.

DOI: https://doi.org/10.1083/jcb.202508040
Nat Struct Mol Biol. 2026 Apr 08.

Microtubules in the axon are GDP bound but adopt a stable GTP-like expanded state.

Elena A Zehr, Shufeng Sun, Stephanie L Sarbanes, Antonina Roll-Mecak.

Microtubules scaffold cells, supporting signaling and cargo transport. They assemble from GTP-tubulin, which hydrolyzes to GDP-tubulin during polymerization. GTP-microtubule lattices are stable; GDP lattices depolymerize rapidly. In vitro, hydrolysis triggers lattice compaction. Lattice spacing regulates motors and microtubule-associated proteins; however, the conformation of tubulin in microtubules in cells is unknown. Here, we present the atomic-resolution cryo-electron microscopy structure of human microtubules in situ, in the axons of human cortical neurons derived from induced pluripotent stem cells (iPS cells). Our 2.7-Å-resolution reconstruction delineates bound water molecules and reveals that axonal microtubules adopt an expanded GTP-like lattice, despite being GDP bound. Using cryo-electron tomography and power spectrum analysis, we find that, unlike in axons, microtubules in undifferentiated iPS cells are compacted. Therefore, lattice expansion is part of neuronal differentiation. Our work provides molecular insights into neurogenesis and has implications for understanding microtubule stability and effector recruitment in neurons.

DOI: https://doi.org/10.1038/s41594-026-01787-7
Nat Commun. 2026 Apr 07. pii: 3161. [Epub ahead of print]17(1):

Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks.

Paris Mazzachi, Ella McDonald, Zarina Greenberg, Alejandra Noreña Puerta, Jenne Tran, Manam Inushi De Silva, Cade Christensen, Robert Adams, Sebastian Loskarn, Helen Beard, Michael Zabolocki, Meera Elmasri, Megan Maack, Kristina L Elvidge, Mark R Hutchinson, Cara O'Neill, Kim M Hemsley, Lisa Melton, Nicholas Smith, Cedric Bardy.

Alterations in synaptic homeostasis are linked to cognitive and behavioural impairments in brain disorders. However, synaptic dysfunction in childhood dementia is poorly understood. Here, we generate human cortical circuits from induced pluripotent stem cells (iPSCs) derived from donors with Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome, a common form of childhood-onset dementia. Action potential firing capacity and morphology of MPS IIIA patient neurons in culture are similar to those of neurons from neurotypical donors. However, long-term neural maturation reveals excitation/inhibition imbalances caused by hyperactive excitatory synapses, disrupted network dynamics, and dysregulated gene expression linked to synaptic homeostasis. This study validates in vitro human neural models to detect neurophysiological phenotypes in childhood dementias and supports drug discovery strategies that target synaptic dysfunction to improve cognition in MPS IIIA and related brain disorders.

DOI: https://doi.org/10.1038/s41467-026-71112-9
Front Immunol. 2026 ;17 1689835

CNS-compartmentalized IgG aggregates and glycosylation in multiple sclerosis contribute to oligoclonal bands and neuronal cytotoxicity.

Sakthi Asokan, Wenbo Zhou, Anthony Fringuello, Tiffany Pointon, Ashley Kennedy, Brendan Freitas, Jackson Tumas French, Haiyan Zhao, Christina Coughlan, Enrique Alvarez, Xiaoli Yu.

   Background: Oligoclonal bands (OCBs) are a hallmark of multiple sclerosis (MS), yet their molecular characteristics and pathogenic relevance remain incompletely understood. Recent evidence suggests that immunoglobulin G (IgG) aggregates and glycosylation may contribute to neuroinflammation and neuronal injury in MS.
Methods: We analyzed paired cerebrospinal fluid (CSF) and plasma samples from MS patients and other neurological controls using transmission electron microscopy, protein aggregation assays, proteomics, isoelectric focusing immunoblotting, and Western blots. Neuronal cytotoxicity was assessed using human iPSC-derived neurons and SH-SY5Y cells. IgG glycosylation was evaluated by enzymatic deglycosylation and lectin-based detection.
Results: We identified large IgG aggregates (> 100 nm) in MS CSF, which were absent in controls and induced complement-dependent neuronal apoptosis. These aggregates were enriched in OCBs and were disrupted by urea or glycine-HCl, resulting in the loss of OCBs. Proteomic analysis revealed enrichment of IgG subclasses and complement components in MS CSF. In addition, MS CSF contained significantly elevated levels of galactosylated and sialylated IgG compared to paired plasma. Enzymatic removal of glycans reduced both OCB intensity and neuronal cytotoxicity.
Conclusions: Our findings demonstrate that CNS-compartmentalized IgG aggregates and glycosylation contribute to the formation of OCBs and neuronal cytotoxicity in MS. These results provide new insights into the molecular basis of OCBs and suggest that targeting IgG glycosylation or aggregation may offer novel therapeutic strategies for MS.

Keywords:  IgG aggregates; autoantibodies; cerebrospinal fluid; complement activation; glycosylation; multiple sclerosis; neuroinflammation; neuronal cytotoxicity

DOI:  https://doi.org/10.3389/fimmu.2026.1689835
bioRxiv. 2026 Apr 01. pii: 2026.03.30.715195. [Epub ahead of print]

Aberrant FICD-mediated AMPylation drives α-Synuclein pathology and overall protein dyshomeostasis in dopaminergic neurons in Parkinson's disease.

Aron Koller, Laura Hoffmann, Alexandra Bluhm, Alina Schweigert, Yanni Schneider, Marie Andert, Tobias Becker, Friederike Zunke, Thomas G Beach, Geidy E Serrano, Steffen Roßner, Jürgen Winkler, Pavel Kielkowski, Wei Xiang.

Background: Filamentation induced by cAMP domain-containing protein (FICD) is an endoplasmic reticulum (ER)-resident adenylyltransferase that catalyzes protein AMPylation, a post-translational modification. Although FICD-mediated AMPylation has been linked to the fine-tuning of proteostasis and neuronal integrity, its role in neurodegenerative diseases characterized by protein dyshomeostasis remains unclear. Parkinson's disease (PD) is defined by dopaminergic neurodegeneration and aggregation of α-synuclein (aSyn) as a consequence of impaired protein homeostasis. We therefore investigated whether dysregulated FICD-mediated AMPylation contributes to PD pathogenesis.
Methods: We combined analyses of human post-mortem PD brain tissue with complementary models, including midbrain dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) of a PD patient carrying an SNCA gene duplication and its isogenic gene dosage-corrected control line, transgenic mouse models of synucleinopathy, and an aSyn-overexpressing H4 neuroglioma cell model. Genetic and pharmacological modulation of FICD activity was integrated with multi-proteomic approaches, including chemical proteomics-based AMPylation profiling, stable isotope labelling with amino acids in cell culture-based global protein turnover analysis, and whole-proteome profiling to identify AMPylation-associated molecular pathways.
Results: FICD was preferentially expressed in dopaminergic neurons and was upregulated in SNCA duplication PD patient-derived neurons, as well as in the basal ganglia of PD post-mortem brains and synucleinopathy mice. Despite this overall increase, the proportion of FICD-expressing dopaminergic neurons was reduced under PD conditions, suggesting selective vulnerability of dopaminergic neurons to FICD. Mechanistically, FICD selectively AMPylated lysosomal proteins, thereby linking AMPylation to the regulation of degradative pathways. Moreover, hyperactivation of FICD-induced AMPylation triggered ER stress, impaired lysosomal function, reduced protein turnover, and ultimately promoted aSyn aggregation and apoptotic cell death. Importantly, pharmacological inhibition of AMPylation reversed aSyn pathology and neurite degeneration in PD patient-derived neurons.
Conclusions: We identify the pathological relevance of FICD-mediated AMPylation in PD-related neurodegeneration and its contribution to aSyn aggregation through a bidirectional interplay with aSyn pathology. Our findings support FICD-mediated AMPylation as a defining molecular switch regulating intracellular protein homeostasis in PD and highlight the FICD-AMPylation pathway as a potential therapeutic target for restoring aSyn pathology and mitigating disease progression.

DOI: https://doi.org/10.64898/2026.03.30.715195
Alzheimers Dement. 2026 Apr;22(4): e71273

Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.

Rachel J Boyd, Daiyun Dong, Ram Sagar, Anton Iliuk, Waqar Ahmed, Xenia Androni, Anton P Porsteinsson, Paul B Rosenberg, Constantine G Lyketsos, Kenneth W Witwer, Vasiliki Mahairaki.

   INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses.
METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects.
RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity.
DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.

Keywords:  Alzheimer disease; clinical heterogeneity; escitalopram oxalate; extracellular vesicle proteomics; extracellular vesicles; induced pluripotent stem cells; proteomic profiling; serotonergic hindbrain organoids

DOI:  https://doi.org/10.1002/alz.71273
bioRxiv. 2026 Mar 13. pii: 2026.03.11.711183. [Epub ahead of print]

Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.

Andrew Caliri, Alejandro Martorell Riera, Akash Saha, Panagiota Kolitsida, Cinta Iriondo Martinez, Samuel Itskanov, Janos Steffen, Carla M Koehler, Alexander M van der Bliek.

Autophagy involves the rapid growth of phagophores through membrane addition. This growth is triggered by vesicles containing the Atg9A protein. However, Atg9A is not incorporated into mature autophagosomes. We now demonstrate that Dynamin-2 (Dnm2) colocalizes with the BAR domain protein Endophilin-B1 (EndoB1/Bif-1/SH3GLB1) and other autophagy proteins when autophagy is induced. Our data suggest that Atg9A is retrieved from phagophores via fission, with Dnm2 acting as the membrane scission protein. Blocking Atg9A recycling, either by mutating Dnm2, using RNA interference, or applying chemical inhibitors, results in Atg9A remaining in autophagosomes and being degraded during autophagy. Overall, these findings provide new insights into the roles of membrane-scission proteins in autophagy.

DOI: https://doi.org/10.64898/2026.03.11.711183
Alzheimers Dement. 2026 Apr;22(4): e71337

Tracking tau and cellular responses in human iPSC-microglia: from uptake to seedable secretion, including in extracellular vesicles.

Maria Kreger Karabova, Anna Del Ser-Badia, Anne Hedegaard, Sam J Washer, Zeynep Baykam, Darragh P O'Brien, Iolanda Vendrell, Svenja S Hester, Roman Fischer, Errin Johnson, Charlotte E Melia, Teige R S Matthews-Palmer, Rishi Matadeen, Alessia Santambrogio, Michael A Metrick, Michele Vendruscolo, Sophie Keeling, Kimberly Ai Xian Cheam, William A McEwan, Kenneth S Kosik, Theresa A Day, William S James, Sally A Cowley.

   INTRODUCTION: Microglia have been implicated in the templated spread of tau aggregates in tauopathies through mouse studies. However, it is unclear whether these findings translate to human disease.
METHODS: We challenged human induced pluripotent stem cell (iPSC)-derived microglia-like-cells (iMGL) with monomeric and fibrillar recombinant tau and tau purified from Alzheimer's patient brains, examining in detail the uptake, processing, release, and seeding of tau by microglia.
RESULTS: iMGL take up tau via lipoprotein receptor-related protein 1 (LRP)1 and heparan sulfate proteoglycans, with leucine-rich repeat kinase 2 affecting LRP1 trafficking. Monomeric tau is digested effectively with minimal effects on iMGL, but recombinant or brain-derived tau fibrils induce chemokine/interferon response subtypes, alongside downregulation of homeostatic genes. Fibrillar tau is degradation-resistant, can escape into the cytoplasm, and becomes phosphorylated on two specific residues. iMGL release partially digested fibrillar tau, including in extracellular vesicles, visualized by cryo-electron microscopy, that seed aggregation in neurons.
DISCUSSION: Our study reveals new insights into human microglial responses to tau, highlighting opportunities to limit pathogenic tau spread.

Keywords:  LRP1; cryo‐electron microscopy; extracellular vesicle; induced pluripotent stem cells; lipoprotein receptor‐related protein 1; microglia; phospho‐proteome; tau

DOI:  https://doi.org/10.1002/alz.71337
Sci Transl Med. 2026 Apr 08. 18(844): eadu9845

A human iPSC model of tauopathies engineered for 4R tau isoform expression endogenously develops late-stage neuronal tau pathology.

Angelika Dannert, Nathalie Schulz, Julien Klimmt, Lea Knez, Bernhard Groschup, Carolina Cardoso Gonçalves, Caterina Carraro, Martina Schifferer, Matthias Brendel, Dominik Paquet.

Tauopathies, such as Alzheimer's disease and frontotemporal dementia, are common neurodegenerative diseases characterized by misfolding, hyperphosphorylation, and aggregation of tau. Molecular mechanisms underlying tauopathies are still poorly understood, which is in part due to a lack of human models autonomously developing major disease hallmarks. The formation of late-stage disease phenotypes may require adult tau isoform expression, which contributes to tau pathogenesis but is challenging to replicate in human stem cell-derived systems, thus impeding research on underlying mechanisms and drug development. Here, we show that induction of adult human brain-like 4R tau isoform expression enables cell-intrinsic formation of late-stage tauopathy hallmarks in induced pluripotent stem cell-derived neurons engineered to contain synergistic tau mutations without exogenous sources of tau pathology. Neurons accumulated seeding-competent and hyperphosphorylated tau in tangle-like structures. Furthermore, exclusive expression of mutant 4R in the absence of the 3R tau isoform disproportionately intensified pathology, resulting in abundant tau misfolding and aggregation. Last, we provide proof of principle that our model can be translationally applied both to test chemical disease modulators and evaluate human tau PET tracers. Collectively, our model corroborates the central role of 4R tau isoform expression for pathogenesis in human neurons and enables investigations to elucidate mechanisms underlying human tauopathy formation. Moreover, it may serve as a platform supporting urgently needed development of disease-modifying drugs.

DOI: https://doi.org/10.1126/scitranslmed.adu9845
Neuropharmacology. 2026 Apr 05. pii: S0028-3908(26)00137-1. [Epub ahead of print]293 110964

Single transient exposure to low-frequency low-intensity electrical stimulation produces ketamine-like effects in human iPSC-derived dopaminergic neurons via Ca2+-dependent BDNF and mTOR signaling.

Giulia Sofia Marcotto, Michela Borghetti, Jonida Bitraj, Laura Cavalleri, Mauro Serpelloni, Michele Zoli, Maurizio Memo, Emilio Sardini, Ginetta Collo.

  Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear. This study aimed to investigate whether brief biphasic low-frequency low-intensity (LF-LI) ES can induce structural and molecular plasticity in human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons, identify the underlying signaling mechanisms, and evaluate its potential to rescue cortisol-induced impairments as in-vitro endocrine model of depression. iPSC-derived dopaminergic neurons were exposed to LF-LI ES using a custom culture-compatible stimulator, and structural plasticity was quantified three days later by computer-assisted morphometry. Pharmacological blockers, quantitative PCR and Western blot analyses were employed to assess calcium influx, brain-derived neurotrophic factor (BDNF)-TrkB-extracellular signal-regulated kinase (ERK)-mTOR signaling, and dopamine D3 auto-receptor roles in mediating LF-LI ES effects. A single 1h LF-LI ES session at 4 mA induced robust increases in maximal dendrite length, primary dendrite number, and soma area, comparable to 1 μM ketamine. LF-LI ES rapidly enhanced ERK and p70-S6K phosphorylation and required L-type voltage-gated calcium channels, TrkB and mTOR, as their inhibition prevented structural remodeling. LF-LI ES increased dopamine D3 auto-receptors mRNA, and its antagonism attenuated LF-LI ES-induced plasticity. In cortisol-treated neurons, LF-LI ES fully reversed dendritic hypotrophy and soma shrinkage. In conclusion, brief LF-LI ES elicits long-lasting, ketamine-like structural and molecular plasticity in human dopaminergic neurons and rescues stress hormone-induced impairments, supporting LF-LI ES-based neuromodulation approaches targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression.

Keywords:  Cortisol; Exogenous electrical stimulation; Induced pluripotent stem cells; Major depressive disorders; Non-pharmacological approach; Stress; Structural plasticity

DOI:  https://doi.org/10.1016/j.neuropharm.2026.110964
Circ Res. 2026 Apr 10. 138(8): e326985

Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.

Xi Fang, Åsa B Gustafsson.

  Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.

Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
J Cell Biol. 2026 Jun 01. pii: e202511133. [Epub ahead of print]225(6):

The SWR1 complex prevents the vacuolar delivery of ATG proteins through a noncanonical pathway.

Siyu Fan, Huan Yang, Jianting Lei, Xinyue Gong, Yiyu Lin, Yuan Zhou, Yuhang Cui, Yuanyuan Ding, Mingzhu Fan, Shan Feng, Weijing Yao, Dong Fang, Kunrong Mei, Hongguang Xia, Cong Yi.

Autophagy is a conserved catabolic process that relies on vacuoles or lysosomes. While autophagosome formation is well characterized, the mechanisms that prevent autophagy-related proteins form being enclosed by the autophagosome and degraded in the vacuole remain unclear in yeast. Here, we show that the SWR1 chromatin remodeling complex plays an essential, noncanonical role in this process. Genome-wide screening identified the SWR1 complex as a critical regulator that prevents the vacuolar delivery of multiple autophagy proteins. This process depends on the structural integrity and ATPase activity of the SWR1 complex. Mechanistically, the SWR1 subunit Rvb1 interacts directly with Atg21, and this interaction is important for SWR1 localization to the phagophore assembly site and efficient protein retrieval. Disruption of the Atg21-Rvb1 interaction results in the vacuolar accumulation of autophagy proteins. These findings uncover an unexpected link between a chromatin remodeling complex and the autophagy machinery, highlighting the Atg21-Rvb1 module as a key regulator of autophagy dynamics in yeast.

DOI: https://doi.org/10.1083/jcb.202511133
bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]

Rab12 is a regulator of mitophagy and mitochondrial homeostasis.

Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.

Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

DOI: https://doi.org/10.64898/2026.03.29.715103
J Cell Biol. 2026 Jun 01. pii: e202509067. [Epub ahead of print]225(6):

The dynamics of centromere assembly and disassembly during quiescence.

Océane Marescal, Kuan-Chung Su, Brittania Moodie, Noah J L Taylor, Iain M Cheeseman.

Quiescence is a state in which cells undergo a proliferative arrest while maintaining their capacity to divide again. Here, we analyze how cells regulate their centromeres during quiescence entry and exit. Despite the constitutive localization of centromere proteins in proliferating cells, cells rapidly disassemble most centromere proteins during quiescence entry while preserving those required to maintain centromere identity. We show that this disassembly occurs primarily through the transcriptional downregulation of centromere proteins. During quiescence exit, the centromere is reassembled during the first S phase to regain normal homeostatic centromere protein levels. CENP-A is typically deposited during G1. However, we find that CENP-A deposition does not occur during the G1 immediately following quiescence exit and instead occurs in the G1 after cells complete their first mitosis. We find that the presence of PLK1 distinguishes these distinct G1 states. These findings reveal centromere dynamics during quiescence entry and exit and highlight paradigms for controlling centromere assembly and disassembly.

DOI: https://doi.org/10.1083/jcb.202509067
Life Sci. 2026 Apr 07. pii: S0024-3205(26)00190-6. [Epub ahead of print] 124381

Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.

Jingjing Wang, Pei Wen, Zhixin Sun, Fengting Gou, Qing Fan, Yuheng He, Deming Zhao, Lifeng Yang.

  Prion diseases are chronic, transmissible, and neurodegenerative disorders that affect both humans and other mammals. Mitophagy is essential for maintaining mitochondrial homeostasis and normal neuronal function. Our previous research show that the PINK1-Parkin-dependent mitophagy pathway is impaired in the PrP106-126 induced prion disease model, yet the underlying downstream mechanisms remain elusive. We report that impaired phosphorylation of ubiquitin at Ser65 diminishes OPTN recruitment to mitochondria, thereby influence mitochondrial translocation of TBK1 and ATG9A, consequently suppresses TBK1 autophosphorylation that depends on the OPTN-ATG9A interaction. As a result, reduction of OPTN phosphorylation dependent on TBK1 inhibits autophagosome formation and ultimately leads to defective mitophagy. Importantly, overexpression of OPTN rescued the mitophagy impairment induced by PrP106-126 and partially restoring mitochondrial morphology and function. Our findings identify OPTN as a critical node, proposing its therapeutic targeting as a strategy to counteract prion disease progression.

Keywords:  Mitophagy; OPTN; Phosphorylation; Prion diseases; TBK1

DOI:  https://doi.org/10.1016/j.lfs.2026.124381
J Huntingtons Dis. 2026 Apr 09. 18796397251410442

Wild-type huntingtin in neurodevelopment.

Laura Lynn Chan, Blair R Leavitt.

  Huntingtin (HTT) is an essential pleiotropic gene. Primarily known for its pathogenic role in Huntington's disease (HD), a progressive autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion located in HTT exon 1 that produces an altered protein product, mutant huntingtin, with an expanded polyglutamine stretch. Despite its monogenic origin, HD has a complex cellular pathology likely due to huntingtin's many protein-protein interactions and diverse functional roles. Wild-type huntingtin loss-of-function may influence HD pathogenesis by intertwining with multiple forms of mutant huntingtin gain-of-function toxicity. Multiple studies have identified irregular neurodevelopmental phenotypes in HD models similar to those due to wild-type huntingtin loss-of-function. Current huntingtin lowering treatment developments suggest that a better understanding of normal HTT functions may be vital for effective therapeutic development. Due to the history of huntingtin gene discovery, most previous reviews have focused on the wild-type huntingtin allele in the context of also inheriting the mutant huntingtin allele. The purpose of this review is to explore wild-type huntingtin's putative function, expression, and variation in neurodevelopment in the absence of the mutant HTT allele, providing a basis to better understand how changes in wild-type huntingtin function may play a role in human health and disease.

Keywords:  ciliogenesis; huntington's disease; lopes-Maciel-Rodan Syndrome; neurodevelopment; neurogenesis; wild-type huntingtin

DOI:  https://doi.org/10.1177/18796397251410442
Circ Res. 2026 Apr 10. 138(8): e326984

Mitochondrial Transfer: From Bench to Bedside.

Gentaro Ikeda, Jiwen Li, Alyssa Wang, Amogha Medha Paleru, Phillip C Yang.

  Intercellular mitochondrial transfer has emerged as a fundamental mechanism of tissue adaptation and repair in the cardiovascular system, with major implications for cardiovascular, neurological, metabolic, and inflammatory diseases. Once thought to be static, mitochondria are now recognized as mobile organelles that move between cells via tunneling nanotubes, extracellular vesicles, and free mitochondria. These pathways support 2 complementary axes of mitochondrial communication: Rescue by Replenish, in which healthy mitochondria or mitochondrial components restore bioenergetics and stress resistance in recipient cells, and Relief by Release, in which damaged mitochondria are exported for degradation to preserve homeostasis and limit inflammation. We summarize the molecular machinery governing tunneling nanotube formation, mitochondria-derived vesicle biogenesis, extracellular vesicle sorting, and free mitochondrial release and uptake, and discuss how these processes shape organ function. Building on these mechanistic insights, we outline 4 translational strategies: (1) cell-based therapies that donate healthy mitochondria or scavenge damaged ones; cell-free approaches using (2) mitochondria-containing extracellular vesicles or (3) purified mitochondria; (4) pharmacological, nutritional, and lifestyle interventions that augment endogenous mitochondrial turnover and intercellular exchange. Finally, we discuss key barriers to clinical translation, including inflammatory and oncogenic risks, mitonuclear incompatibility, incomplete understanding of the fate and durability of transferred mitochondria, and the lack of standardized manufacturing, potency assays, and long-term storage methods. Continued integration of mechanistic biology with bioengineering and regulatory science will be essential to safely move mitochondrial transfer-based therapies from bench to bedside in cardiovascular medicine.

Keywords:  cell communication; energy metabolism; extracellular vesicles; homeostasis; inflammation; mitochondria; nanotubes

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326984