bims-axbals 2026-04-19 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–04–19
28 papers selected by
TJ Krzystek

Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.
Nuclear export modulates TDP-43 phase transitions and cytoplasmic aggregation.
External mechanical force drives axonal cytoskeletal rearrangements.
Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons.
Microprotein Regulates G-quadruplex Driven RNA Aggregation.
An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.
Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.
Worm orthologues of cytokinesis-associated proteins CIT and ASPM regulate neuronal microtubule dynamics and polarity in C. elegans.
Loss of schizophrenia risk gene XPO7 disrupts neuronal excitability and network regularity via altered Na+ channel dynamics in human neurons.
LIS1 is critical for axon integrity in adult mice.
GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.
A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
Evaluating the peripheral nervous system pathology of Alzheimer's disease utilizing a functional human NMJ microphysiological system.
Immaturity of the neuromuscular junction in spinal muscular atrophy mouse models.
Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.
Stem cells enhance mitochondrial function in experimental Huntington's disease.
Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons.
Disentangling Intelligence and Consciousness in Human Brain Organoids.
Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice.
Regulation and function of interstitial axon branching in cortical projection neurons.
Nuclear speckle dynamics are controlled by polyphosphate inhibition of CLK proteins.
Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.
Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.
Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease.
Palmitoylation of Tspan4 is essential for migrasome formation.
Locally synthesized glycyl aminoacyl-tRNA synthetase is important for local translation in neurons.
Neurogranin Promotes Neuronal Maturation and Network Activity Through Ca2+/Calmodulin Signaling.

Biochem Biophys Res Commun. 2026 Apr 09. pii: S0006-291X(26)00487-0. [Epub ahead of print]818 153723

Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.

Ratna Priya, Goutam Kumar Tanti, Buddhi Prakash Jain.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weakness, paralysis, and respiratory failure. Dysregulation of RNA metabolism and splicing has emerged as a central mechanism in ALS pathogenesis. TARDBP (TAR DNA-binding protein), FET family proteins (FUS, EWSR1, TAF15), SOD1 (Superoxide Dismutase 1), and C9orf72 (Chromosome 9 Open Reading Frame 72) are key genes associated with ALS that regulate RNA processing, alternative splicing, and nuclear-cytoplasmic transport. Mutations or mislocalization of these proteins result in nuclear loss-of-function and cytoplasmic gain-of-function toxicity, promoting protein aggregation, sequestering spliceosomal components, and impairing spliceosome assembly. This leads to the aberrant inclusion of cryptic exons in essential neuronal genes, such as STMN2 (Stathmin 2) and UNC13A (Unc-13 Homolog A), resulting in the production of truncated proteins, defective axonal maintenance, and impaired synaptic function. TDP-43 pathology, a hallmark of ALS, disrupts splicing and RNA transport, while C9orf72 repeat expansions and FET protein mutations exacerbate cytoplasmic aggregation and stress granule dynamics. Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical studies. Complementary approaches, including the inhibition of stress kinases and the activation of autophagy, reduce cytoplasmic protein aggregation and support neuronal homeostasis. This review provides a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS. Understanding the interplay among splicing defects, RNA-binding protein pathology, and neuronal degeneration is critical for developing next-generation multimodal therapies to restore RNA processing, reduce toxic protein accumulation, and promote motor neuron survival.

Keywords:  Alternative splicing; Amyotrophic lateral sclerosis; Exon; RNA binding proteins; RNA processing

DOI:  https://doi.org/10.1016/j.bbrc.2026.153723
bioRxiv. 2026 Apr 12. pii: 2025.12.16.694670. [Epub ahead of print]

Nuclear export modulates TDP-43 phase transitions and cytoplasmic aggregation.

Natalie Chin, Qi Zhang, Jizhong Zou, Ken Chih-Chien Cheng, Wei Zheng, Yihong Ye.

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase behavior may influence its aggregation propensity and neurotoxic activity. The mechanism(s) that modulates the transition of TDP-43 from a liquid to solid phase is poorly defined. Here we combine chemical and genome-wide genetic screenings to identify cellular factors that modulate the phase behavior of an RNA-binding defective TDP-43 mutant that mimics an Amyotrophic Lateral Sclerosis (ALS)-associated variant. Our screens uncover multiple cellular processes including RNA splicing, protein translation, proteostasis imbalance and nuclear export as TDP-43 phase regulators. Importantly, TDP-43 phase transition can be dynamically recapitulated in vitro in a semi-permeabilized cell system, which reveals that the inhibition of nuclear export reshapes the nuclear environment in favor of an RNA-dependent TDP-43 liquid-liquid phase separation (LLPS) state, which mitigates cytoplasmic TDP-43 aggregation. We validated this mechanism in a brain organoid model bearing an ALS-associated mutation, showing that nuclear export deficiency can limit pathogenic phospho-TDP-43 accumulation. These findings establish nuclear export as a key regulator of TDP-43 phase transitions and define a mechanistic framework that links altered nuclear transport and phase dynamics to TDP-43 aggregation potential.

DOI: https://doi.org/10.64898/2025.12.16.694670
Curr Biol. 2026 Apr 16. pii: S0960-9822(26)00373-8. [Epub ahead of print]

External mechanical force drives axonal cytoskeletal rearrangements.

Grace L Swaim, Oliver V Glomb, Yi Xie, Chloe Emerson, Zhuoyuan Li, Daniel Beaudet, Adam G Hendricks, Shaul Yogev.

  Axons experience strong mechanical forces due to animal movement. These forces serve as sensory cues in mechanosensory neurons, but their impact on other neuron types remains poorly defined. Here, we uncover an axonal response to external physiological forces that plays a key role in axon integrity. Using cell-specific degradation alleles and chemogenetic silencing, we find that Talin, RhoA, and non-muscle myosin II function in a C. elegans motor neuron axon in response to forces generated by muscle contraction. In control animals, this response promotes cytoskeletal continuity by regulating the local oscillatory behavior of individual microtubule polymers. When the structural integrity of the axon is compromised by disrupting the spectrin-based membrane-associated skeleton, excessive RhoA activity promotes axon breakage. This phenotype is accompanied by mislocalized F-actin and myosin and conversion of local microtubule oscillations to robust movements that generate large cytoskeletal discontinuities. Importantly, reducing the mechanical force on the axon or degrading neuronal RhoA restores cytoskeletal continuity and prevents axon breakage in spectrin mutants. These results uncover an axonal mechanism that controls cytoskeletal continuity and axon integrity in response to external mechanical forces.

Keywords:  F-actin; RhoA; axon; cytoskeleton; mechanotransduction; microtubule; myosin; neuron; spectrin; talin

DOI:  https://doi.org/10.1016/j.cub.2026.03.053
Sci Signal. 2026 Apr 14. 19(933): eadx6752

Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons.

Jose Norberto S Vargas, Anna-Leigh Brown, Kai Sun, Cathleen Hagemann, Bethany Geary, David Villarroel-Campos, Sam Bryce-Smith, Matteo Zanovello, Madeline Lombardo, Stan Majewski, Andrew Tosolini, Maria Secrier, Matthew J Keuss, Andrea Serio, James N Sleigh, Pietro Fratta, Giampietro Schiavo.

The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i3 LMNs). Metabolic RNA sequencing (SLAM-seq) and phosphoproteomic profiling of i3 LMNs revealed that BDNF temporally regulated the expression and RNA stability of functionally distinct transcriptional programs that included regeneration-associated gene sets, further enhancing their expression. BDNF also regulated the phosphorylation of multiple proteins involved in cytoskeletal dynamics. In compartmentalized cultures of neurons, in which microfluidic chambers isolate somata from their axons, BDNF-induced regeneration depended on axon-specific activation of the ERK-RSK-S6K kinase pathway. The findings show that extrinsic BDNF signaling coordinates intrinsic axon-regeneration programs and highlight the role of spatially regulated kinase activation in this process.

DOI: https://doi.org/10.1126/scisignal.adx6752
bioRxiv. 2026 Apr 15. pii: 2026.04.10.717804. [Epub ahead of print]

Microprotein Regulates G-quadruplex Driven RNA Aggregation.

Bikash R Sahoo, Janakraj Bhattrai, Arnav Sharma, Ursula Jakob, James Ca Bardwell.

Repeat expansions of the hexanucleotide GGGGCC in C9orf72 form aberrant phase transitions that have been linked to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. RNA structures such as G-quadruplexes and hairpins play important roles in these processes. Here, we show that the human microprotein ZNF706 acts as a modulator of G-quadruplex formation and RNA phase behavior. ZNF706 antagonizes pathological gel-solid transitions by melting hexanucleotide repeat G-quadruplex structures converting gel-like aggregates into more dynamic condensates. Loss of ZNF706 enhances the cellular production clearance of hexanucleotide repeat-mediated dipeptide repeat proteins, while overexpression suppresses their production and promotes clearance. Mechanistically, ZNF706 influences hexanucleotide repeat condensate fluidity and viscoelasticity. We find ZNF706 acts as an RNA chaperone that remodels repeat RNA structures and solubilizes RNA aggregates. This activity represents one mechanism whereby cells can regulate G-quadruplex driven phase transitions linked to neurodegenerative diseases.

DOI: https://doi.org/10.64898/2026.04.10.717804
Protein Sci. 2026 May;35(5): e70565

An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.

Emily J Byrd, Joel A Crossley, Chalmers C C Chau, Paolo Actis, Antonio N Calabrese.

  TAR DNA-binding protein 43 (TDP-43) plays a critical role in RNA metabolism and is incorporated into biomolecular condensates called stress granules. In amyotrophic lateral sclerosis (ALS) and several other neurodegenerative disorders, TDP-43 undergoes aberrant phase transitions, forming insoluble amyloid aggregates, including fibrils composed of solely its intrinsically disordered C-terminal domain (CTD). Despite its central role in disease, the conformational dynamics of the CTD remain poorly understood due to its heterogeneous and transient conformational landscape. Here, we employ native ion mobility-mass spectrometry (IM-MS) using nanopipette sub-micron nano electrospray ionization (nanoESI) emitters to characterize the conformational landscape of wild-type and ALS-associated TDP-43 CTD variants (Q331K and R361S) under different solution conditions. Our data suggest that mutations and salt concentration modulate the CTD's conformations. Combined with thioflavin T fluorescence, light scattering, and microscopy, we reveal that these conformational shifts correlate with altered amyloid assembly kinetics and propensity to form condensates. Notably, the Q331K variant, which has a mutation in the transient α-helical region in the CTD, has reduced propensity to form biomolecular condensates but can undergo amyloid assembly in the absence of condensate formation, suggesting that sequence alterations in this α-helical region can tune the molecular mechanism of amyloid assembly. This study demonstrates the power of IM-MS in probing disordered proteins and reveals mechanistic insights into how disease-associated mutations differentially tune TDP-43 CTD amyloid assembly mechanisms.

Keywords:  Ion mobility–mass spectrometry; TDP‐43 C‐terminal domain; amyloid assembly; biomolecular condensates; intrinsically disordered proteins

DOI:  https://doi.org/10.1002/pro.70565
Neural Regen Res. 2026 Apr 14.

Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.

Valentina Tedeschi, Raffaella Ciancio, Silvia Piccirillo, Alessandra Preziuso, Tiziano Serfilippi, Valentina Terenzi, Simona Magi, Vincenzo Lariccia, Pasqualina Castaldo, Antonio Vinciguerra, Ilaria Piccialli, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo.

  Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.

Keywords:  ; autophagy; channels; endoplasmic reticulum; endoplasmic reticulum stress; lysosome; mitochondria; mitochondria-associated membranes; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01754
PLoS Genet. 2026 Apr 15. 22(4): e1012106

Worm orthologues of cytokinesis-associated proteins CIT and ASPM regulate neuronal microtubule dynamics and polarity in C. elegans.

Sunanda Sharma, Keerthana Ponniah, Ishanee Bandyopadhyay, Devyani Vadawale, Sandhya P Koushika, Anindya Ghosh-Roy.

The polarized architecture of neurons is intricately associated with the modulation of microtubule dynamics. Over the years, several microtubule-associated factors that regulate neuronal polarity have been identified. However, the precise details of how microtubule arrangement and stability are established in axons and dendrites are not clearly understood. To uncover the relevant factors involved in the biological pathways governing microtubule regulation in neurons, we conducted a suppressor screen using the neuronal ectopic extension phenotype caused by the loss of the kinesin-13 family microtubule depolymerizing protein KLP-7 in C. elegans. Interestingly, apart from eleven variants of α (mec-12) and β (mec-7) tubulins, we isolated a variant of cytokinesis-associated protein, W02B8.2/citk-1, the suggested kinase-less orthologue of mammalian citron-rho interacting kinase (CIT). Little is known about the role of CIT in microtubule regulation in post-mitotic neurons. In this study, we found that the kinase-less worm orthologues of CIT, citk-1 and citk-2, redundantly modulate microtubule stability in the axon-like anterior process and maintain the population of plus-end-out microtubules in the dendrite-like posterior process of the PLM mechanosensory neurons in a cell-autonomous manner. In the absence of citk-1 and citk-2, PLM neurons exhibit variable morphological defects, including neurite growth and synaptic branch defects. Moreover, we find that CITK-1/2 work in the same genetic pathway as ASPM-1 (the worm homolog of mammalian ASPM (abnormal spindle-like microcephaly-associated protein)) to modulate plus-end dynamics of microtubules in PLM neurons. Our findings suggest that the cytokinesis-associated CITK-1/2 and ASPM-1 have non-mitotic roles in regulation of microtubules in differentiated PLM neurons.

DOI: https://doi.org/10.1371/journal.pgen.1012106
Mol Psychiatry. 2026 Apr 15.

Loss of schizophrenia risk gene XPO7 disrupts neuronal excitability and network regularity via altered Na+ channel dynamics in human neurons.

Lei Cui, Erkin Kurganov, Derek Hawes, Philipp Hornauer, Raozhou Lin, Yining Wang, Andreas Hierlemann, Morgan Sheng, Ralda Nehme, Jen Q Pan.

Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional consequences of XPO7 loss of function (LoF) in human induced pluripotent stem cell (iPSC)-derived neurons, focusing on its role as a schizophrenia risk gene identified through recent large-scale exome sequencing analyses. By integrating high-precision electrophysiological measurements with transcriptomic, proteomic, and imaging approaches, we demonstrate that XPO7 LoF alters Na+ channel properties and availability, disrupts neuronal excitability, and impairs the synchrony and regularity of network activity. These functional deficits are accompanied by widespread molecular dysregulation affecting nucleocytoplasmic transport, ion channel function, and synaptic composition. Among the dysregulated proteins is Nav1.2, a voltage-gated sodium channel encoded by SCN2A, which displays aberrant subcellular distribution in XPO7 LoF neurons. Together, these findings position XPO7 as a critical regulator of neuronal excitability and connectivity, linking channelopathy to cellular phenotypes relevant to schizophrenia pathophysiology.

DOI: https://doi.org/10.1038/s41380-026-03587-3
J Neurosci. 2026 Apr 17. pii: e1971252026. [Epub ahead of print]

LIS1 is critical for axon integrity in adult mice.

Samaneh Matoo, Anne M Ventrone, Shreena Patel, Jack K Otterson, Sean Noonan, Noah Leever, Timothy J Hines, Ashley L Kalinski, Deanna S Smith.

Mutations in human LIS1 cause lissencephaly, a severe developmental brain malformation. Although most studies focus on development, LIS1 is also expressed in adult mouse tissues. We previously induced LIS1 knockout (iKO) in adult mice using a Cre-Lox approach with an actin promoter driving CreERT2 expression. This proved to be rapidly lethal, with evidence pointing toward nervous system dysfunction. CreERT2 activity was observed in astrocytes, brainstem and spinal motor neurons, and axons and Schwann cells in the sciatic and phrenic nerves, suggesting dysfunctional cardiorespiratory and motor circuits. However, it is unclear how LIS1 knockout in these different cell types contributes to the lethal phenotype. We now report that LIS1 depletion from astrocytes is not lethal to mice (male or female), although glial fibrillary protein (GFAP) expression is increased in all LIS1-depleted astrocytes. In contrast, LIS1 depletion from projection neurons causes motor deficits and rapid lethality in both males and females. This is accompanied by progressive, widespread axonal degeneration along the entire length of both motor and sensory axons. Interestingly, sensory neurons harvested from iKO mice initially extend axons in culture but soon develop axonal swellings and fragmentation, indicating axonal degeneration. LIS1 is a prominent regulator of cytoplasmic dynein 1 (dynein, hereafter), a microtubule motor whose disruption can cause both cortical malformations and later-onset neurodegenerative diseases, such as Charcot-Marie-Tooth disease. Our results raise the possibility that LIS1 depletion, through disruption of dynein function in mature axons, may lead to Wallerian-like axon degeneration without traumatic nerve injury.Significance Statement A healthy nervous system requires that proper brain wiring is maintained throughout the life of the animal. Connectivity often involves the long axons of projection neurons. Some axons drive cognition, others contribute to sensory and motor systems, while still others subserve vitally important cardiorespiratory processes. We show that LIS1, a protein linked to congenital brain abnormalities, also plays a crucial role in fully developed projection neurons in the adult mouse. LIS1 depletion from these cells causes severe axonal degeneration resembling the Wallerian degeneration that occurs in response to nerve injury. Because LIS1 regulates dynein, and because defective dynein can cause neurodegenerative disorders in humans, our study suggests that drugs targeting Wallerian degeneration may have therapeutic potential for dynein-related diseases.

DOI: https://doi.org/10.1523/JNEUROSCI.1971-25.2026
EMBO Rep. 2026 Apr 16.

GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.

Julian Nüchel, Maryam Omidi, Stephanie A Fernandes, Marina Tauber, Sandra Pohl, Markus Plomann, Constantinos Demetriades.

Lysosomes are multifunctional organelles that play important roles in cellular recycling, signaling, and homeostasis, relying on precise trafficking and activation of lysosomal enzymes. While the Golgi apparatus plays a central role in lysosomal enzyme sorting, the mechanisms linking Golgi function to lysosomal activity remain incompletely understood. Here, we identify the Golgi-resident protein GRASP55, but not its paralog GRASP65, as necessary for lysosome function. Loss of GRASP55 expression leads to missorting and secretion of lysosomal enzymes, lysosomal dysfunction and bloating. GRASP55 deficiency also disrupts lysosomal mTORC1 signaling, reducing the phosphorylation of its lysosomal substrates TFEB/TFE3, while sparing its non-lysosomal targets. Mechanistically, GRASP55 binds and maintains the COPI adaptor GOLPH3 protein at the Golgi, thereby controlling the Golgi localization and stability of LYSET and GNPTAB that are required for mannose 6-phosphate (M6P) tagging of lysosomal enzymes. These findings reveal an essential role for GRASP55 in Golgi-lysosome communication and lysosomal enzyme trafficking and underscore the importance of Golgi-mediated protein sorting in lysosome function and lysosomal mTORC1 signaling.

DOI: https://doi.org/10.1038/s44319-026-00773-w
J Cell Sci. 2026 Apr 13. pii: jcs.264577. [Epub ahead of print]

A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.

Riccardo Babic, Leon Lucya, Christoph Reiter, Franziska Kriegenburg, Ramón Castellanos-Martínez, David M Hollenstein, Florian Becker, Carola Hunte, Claudine Kraft.

  Mitophagy, the selective degradation of damaged mitochondria, preserves mitochondrial quality, yet how mitochondrial fission is coordinated with autophagy initiation remains unclear. Here we identify the mitochondrial outer membrane protein MTFR1L as a key component of mitophagy initiation hubs after using a synthetic FKBP-FRB system to tether ULK1 kinase to mitochondria independently of damage. We find that MTFR1L is enriched at ULK1 foci together with additional fission factors and constitutive mitochondrial targeting of MTFR1L shifts mitochondrial morphology towards fragmentation. MTFR1L depletion decreases respiratory capacity, elevates apoptosis, and impairs mitophagy flux. Upon mitophagy induction, MTFR1L is phosphorylated in a ULK1 kinase-dependent manner, and reciprocally modulates ULK1 activity, establishing a feedback loop. Moreover, MTFR1L is required for proper ATG13 stability. These findings position MTFR1L as a critical link between mitochondrial fission and the autophagy machinery, coordinating mitophagy initiation and cell survival.

Keywords:  ATG13; Autophagy; MTFR1L; Mitophagy; ULK1

DOI:  https://doi.org/10.1242/jcs.264577
Alzheimers Dement. 2026 Apr;22(4): e71281

Evaluating the peripheral nervous system pathology of Alzheimer's disease utilizing a functional human NMJ microphysiological system.

Akhmetzada Kargazhanov, Romy Aiken, Kenneth Hawkins, Rafael Lopez, Ahmad Nawaz, Gaurav Srivastava, Chase Miller, Will Bogen, Christopher Long, David Morgan, Xiufang Guo, James Hickman.

   INTRODUCTION: Alzheimer's Disease (AD) is a central nervous system (CNS) neurodegenerative disease leading to dementia, but can also show symptoms of motor deficits. It is not clear whether the peripheral motor deficits in AD are derived from upstream centers or intrinsic to the neuromuscular circuit. This study developed a model to evaluate the neuromuscular pathology of familial AD (fAD) in a functional neuromuscular junction (NMJ) system.
METHODS: The fAD iPSC motoneurons (MNs), together with healthy iPSC skeletal myoblasts (SKM), were adapted into a dual chamber NMJ system. The formation and function of the NMJs formed were evaluated utilizing clinically translatable readouts.
RESULTS: Functional analysis indicated that NMJs formed with fAD MNs showed severe (PSEN1 A246E) to moderate (APP K595N/M596L) deficiencies in NMJ function.
DISCUSSION: These findings confirmed that fAD mutations lead to NMJ deficiencies, supporting that motor deficits can be induced independently from cognitive deficits.

Keywords:  fAD NMJ pathology; familial Alzheimer's disease; microphysilogical system; motoneurons; neuromuscular junction; peripheral nervous system

DOI:  https://doi.org/10.1002/alz.71281
Front Cell Neurosci. 2026 ;20 1795130

Immaturity of the neuromuscular junction in spinal muscular atrophy mouse models.

Lucía Tabares, Andrea Fuentes-Moliz, Raquel Cano, Rocío Ruiz, Saravanan Arumugam.

  Spinal muscular atrophy (SMA) is caused by deficiency of the survival motor neuron (SMN) protein and is classically defined by degeneration of lower motor neurons. Extensive evidence from mouse models and human tissue demonstrates that dysfunction at the neuromuscular junction (NMJ) emerges early and precedes overt denervation. Here, we review structural, molecular, and functional studies showing that SMA NMJs fail to complete key postnatal maturation programmes that normally scale presynaptic release capacity to muscle growth and increasing functional demand. SMA motor terminals retain multiple features of developmental immaturity, including reduced active zone number, limited synaptic vesicle pool extension, altered cytoskeletal organisation, incomplete molecular specialization, and impaired recruitment of functional release sites, resulting in constrained neurotransmitter release and reduced presynaptic reserve. These defects are highly muscle- and region-specific and preferentially affect vulnerable motor units. We propose a conceptual framework in which delayed and incomplete NMJ maturation increases susceptibility to superimposed degenerative processes, ultimately leading to synaptic destabilisation and denervation. This integrated view reconciles early synaptic dysfunction with later neurodegeneration and has important implications for understanding SMA pathogenesis, identifying sensitive biomarkers, and optimizing the timing and targets of therapeutic intervention.

Keywords:  active zones; calcium channels; motor neurondevelopment; neuromuscular junction; spinal muscular atrophy; synaptic maturation; synaptic vesicles

DOI:  https://doi.org/10.3389/fncel.2026.1795130
Nat Genet. 2026 Apr 15.

Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.

Zinan Zhou, Junho Kim, August Yue Huang, Matthew Nolan, Junseok Park, Ryan Doan, Taehwan Shin, Michael B Miller, Mingyun Bae, Boxun Zhao, Jinhyeong Kim, Brian Chhouk, Katherine Morillo, Rebecca C Yeh, Connor Kenny, Jennifer E Neil, Chao-Zong Lee, Takuya Ohkubo, John Ravits, Olaf Ansorge, Lyle W Ostrow, Clotilde Lagier-Tourenne, Eunjung Alice Lee, Christopher A Walsh.

Although mutations in many genes cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), most cases are sporadic (sALS and sFTD) with unclear etiology. Here we tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-sequencing data from an additional cohort identified deleterious somatic variants in DYNC1H1 and LMNA, genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.

DOI: https://doi.org/10.1038/s41588-026-02570-6
Stem Cells. 2026 Apr 09. pii: sxag019. [Epub ahead of print]

Stem cells enhance mitochondrial function in experimental Huntington's disease.

Francesco D'Egidio, Napasiri Putthanbut, Michaela Starahs, Jea Young Lee, Cesario V Borlongan.

  Huntington's Disease (HD) is a neurodegenerative disorder caused by CAG triplet expansion in the HTT gene, producing a mutant Huntingtin protein that impairs mitochondrial dynamics by reducing fusion and increasing fission. Mesenchymal stem cells (MSCs) have shown potential therapeutic effects by sharing functional mitochondria and other secretomes. In this study, quinolinic acid-lesioned neuro-2a (QA-N2a) cells and glutamatergic neurons with 50 CAG repeats (HD neurons) were co-cultured with human umbilical cord-derived MSCs for 5 hours. For QA-N2a cells, immunocytochemistry was performed to demonstrate change in GABA and Substance P before and after co-culture. For HD neurons, immunocytochemistry was conducted to identify mitochondrial proteins, while Western Blot was employed to evaluate proteins related to inflammation and mitochondrial function. As a result, co-culture with MSC significantly restored the expression of GABA and Substance P, which diminished after QA exposure. In HD neurons co-cultured with MSCs, an increase in mitochondrial abundance was observed, with significantly higher intensity and dendritic distribution of mitochondria compared to control cells. Western Blot analysis confirmed this increase and showed a rising trend in ATP5a levels. MSCs also promoted mitochondrial fusion, indicated by higher levels of Mitofusin 2 (MFN2) and Mitochondrial Dynamin Like GTPase (OPA1), and a trend of reduction in the fission marker Dynamin-Related Protein (DRP1). Additionally, the co-culture led to a decreased trend in neuroinflammation markers IL-6, TNF-α, MMP9, and p-NFkB. Collectively, this study demonstrates that MSCs alleviate HD pathology by restoring mitochondria activity and potentially suppressing inflammation in two different HD in vitro models.

Keywords:  Huntington’s disease; cell-free therapy; mesenchymal stem cells; mitochondrial transfer; secretome

DOI:  https://doi.org/10.1093/stmcls/sxag019
Front Cell Dev Biol. 2026 ;14 1755814

Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons.

Ming Qi, Nan Hu, Jianfeng Ding, Jingwen Niu, Bo Long, Mingsheng Liu.

   Objective: To explore the dynamic changes in excitability and viability of induced pluripotent stem cells (iPSC)-derived motor neurons from sporadic amyotrophic lateral sclerosis (ALS) and compare them with SOD1-related ALS patients and healthy control.
Methods: Peripheral blood samples were collected from ALS patients and healthy controls (HC) to establish the iPSC-derived motor neurons (MNs). Whole-cell patch-clamp recordings at different culture stages was made using an Axopatch 700B amplifier in combination with pClamp 11 software (Molecular Devices). The frequency of action potentials (APs) was recorded. Additionally, Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) Nick-End Labeling (TUNEL) was used to assess the apoptosis of MNs.
Results: ALS patient-derived MNs exhibited significantly higher firing rates compared to HCs at both 4-7 weeks (p = 0.004) and 7-9 weeks (p = 0.009). Further analysis revealed that SOD1-derived MNs showed significantly higher firing frequencies than sALS (p = 0.009) and HCs (p < 0.001) in 4-7 weeks. In 7-9 weeks, it remained significant between SOD1 and HC-derived MNs (p = 0.015), but became insignificant between SOD1 and sALS (p = 0.855). The apoptotic rate of sALS (Day 30: 61.37% ± 9.63%; Day 60: 78.41% ± 6.63%) and SOD1 (Day 30: 73.69% ± 8.81%; Day 60: 60.37% ± 11.53%) -derived MNs was significantly higher than those of HCs at both Day 30 (30.72% ± 7.57%) and Day 60 (50.85% ± 19.36%) (p < 0.001).
Conclusion: MNs derived from both patients with mutant SOD1 and sporadic ALS exhibited increased excitability compared to HCs. The increased excitability of MNs derived from ALS patients with mutant SOD1 occurred earlier, and over time, became consistent with the excitability observed in MNs derived from sporadic ALS. The apoptosis rates of MNs showed similar trends. iPSC-derived MNs from both sporadic and mutant ALS may serve as useful cell models for ALS in future studies.

Keywords:  ALS; IPSC; apoptosis; hyperexcitability; motor neuron (MN)

DOI:  https://doi.org/10.3389/fcell.2026.1755814
AJOB Neurosci. 2026 Apr-Jun;17(2):17(2): 124-126

Disentangling Intelligence and Consciousness in Human Brain Organoids.

Nada S Salem.

DOI: https://doi.org/10.1080/21507740.2026.2649187
Sci Transl Med. 2026 Apr 15. 18(845): eaea4205

Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice.

Yixiang Jiang, Amber M Tetlow, Yan Lin, Changyi Ji, Jack Ader, Klaudia F Laborc, Adam C Mar, Ruimin Pan, Xiang-Peng Kong, Erin E Congdon, Einar M Sigurdsson.

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

DOI: https://doi.org/10.1126/scitranslmed.aea4205
Trends Neurosci. 2026 Apr 15. pii: S0166-2236(26)00053-6. [Epub ahead of print]

Regulation and function of interstitial axon branching in cortical projection neurons.

Jakub Ziak, Sriram Sudarsanam, Alex L Kolodkin.

  Nervous system function is contingent on accurate neuronal connectivity patterns. A single neuron must often connect with multiple synaptic partners. Excitatory cortical projection neurons in the mammalian brain are a prime example of neurons whose axons innervate multiple distant target regions. This is made possible, in part, by interstitial axon branches that extend from axon shafts during development. The identification of molecular mechanisms that regulate interstitial axon branching in cortical projection neurons remains a major challenge. In this review, we summarize known stereotyped interstitial axon branching patterns in the mammalian brain and their spatiotemporal and molecular developmental cues. Taken together, these discoveries provide a foundation for understanding and identifying the molecular determinants that direct cortical connectivity during neural development.

Keywords:  cell signaling; cerebral cortex; cortical development; cortical lamination; excitatory pyramidal neurons; neuronal membrane

DOI:  https://doi.org/10.1016/j.tins.2026.03.007
Nucleic Acids Res. 2026 Apr 13. pii: gkag309. [Epub ahead of print]54(7):

Nuclear speckle dynamics are controlled by polyphosphate inhibition of CLK proteins.

Blanca Lázaro, Francisco J Tadeo, Andrea Rodríguez, Lucía Ayuso-Molina, Joan Marc Martínez-Láinez, Eva Quandt, Maribel Bernard, Filipy Borghi, Adolfo Saiardi, Jonàs Juan-Mateu, Javier Jiménez, Josep Clotet, Samuel Bru.

Nuclear speckles (NS) are membraneless nuclear organelles that act as critical hubs for pre-messenger RNA splicing. Defects in splicing are linked to several human diseases, including cancer, Alzheimer's disease, and dystrophies. While CLK kinases regulate the mobilization of splicing factors from NS, the molecular mechanisms underlying NS assembly and dissolution remain unclear. Using an adaptation of the Biotinylation by Antibody Recognition technique, we identified polyphosphate (polyP) as a novel and essential regulator of NS dynamics. Polyphosphate, a highly conserved polyanion composed of a chain of phosphate molecules, is involved in several functions in mammalian cells. Here, we show that polyP interacts with the NS core component SRRM2, and its depletion disrupts NS organization releasing splicing factors into the nucleoplasm. RNA-seq analysis reveals that polyP depletion increases exon exclusion, particularly in transcripts with multiple isoforms, highlighting its role in splicing regulation. Mechanistically, we demonstrate that polyP acts as a physiological inhibitor of CLK3 kinase, preventing the phosphorylation of SR proteins and thereby maintaining NS stability. Our findings not only expand our understanding of NS biology but also provide new insights into the polyP involvement in splicing-related diseases.

DOI: https://doi.org/10.1093/nar/gkag309
bioRxiv. 2026 Apr 07. pii: 2026.04.04.716514. [Epub ahead of print]

Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood 1-6 . Mitochondrial dysfunction is a common feature of tauopathies 7,8 . Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to tau's physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD + /NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2026.04.04.716514
Nat Commun. 2026 Apr 11. pii: 3436. [Epub ahead of print]17(1):

Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.

Kerstin Filippi, Kathrin Graf-Riesen, Maithreyan Kuppusamy, Andreas Unger, Kenichi Kimura, Martin Matijass, Henrique Baeta, Magdalena Podlacha, Daniel Haertter, Alexei P Kudin, Martin Wiemann, Grzegorz Węgrzyn, Cornelia Kornblum, Jens Reimann, Wolfgang A Linke, Pitter F Huesgen, Wolfram S Kunz, Bernd K Fleischmann, Michael Hesse.

Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.

DOI: https://doi.org/10.1038/s41467-026-71749-6
Cell Death Discov. 2026 Apr 15.

Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.

Ruchi Umargamwala, Jantina Manning, Julian M Carosi, Donna Denton, Sharad Kumar.

Autophagy is a fundamental cellular recycling process that maintains homeostasis during animal development and under nutrient-limiting conditions. In our previous work, we employed autophagy-dependent cell death (ADCD) in the obsolete Drosophila larval midgut as a model to identify the enzymes involved in protein modification via ubiquitination with potential roles in autophagy regulation. From a genetic screen we identified RING E3 ligase RCHY1 as a candidate regulator. Here, we demonstrate that RCHY1 is essential for autophagy regulation during larval midgut ADCD in Drosophila and promotes autophagic flux in HeLa cells. Loss of Rchy1 impaired autophagosome-lysosome fusion and led to the accumulation of amphisomes in larval midgut cells. Similarly, depletion of RCHY1 in HeLa cells disrupted autophagic flux and reduced autolysosome formation, indicating evolutionary conservation of its function. Collectively, our findings identify RCHY1 as a putative regulator of autophagy that facilitates autophagosome-lysosome fusion.

DOI: https://doi.org/10.1038/s41420-026-03088-w
Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2504764123

Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease.

Simona Brillante, Mariagrazia Volpe, Anna Diana, Santiago Negueruela, Marta Molinari, Rosa Saurino, Eva Cipollaro, Elena Polishchuk, Erika Tenderini, Carla Damiano, Patrizia Tornabene, Roman Polishchuk, Giancarlo Parenti, Antonietta Tarallo, Sandro Banfi, Ivana Trapani, Sabrina Carrella, Alessia Indrieri.

  Stargardt disease type 1 (STGD1) is the most common hereditary macular degeneration. It is caused by mutations in ABCA4, which result in the progressive degeneration of the retinal pigment epithelium (RPE), ultimately leading to photoreceptor loss. Despite extensive efforts, STGD1 currently lacks effective treatments. Here, we first identified mitochondrial defects in the photoreceptors of Abca4-/- mice and STGD1 patient-derived retinal organoids. Specifically, we found reduced mitochondrial content, defective cristae morphology, and downregulation of OPA1, a critical regulator of mitochondrial integrity, demonstrating that photoreceptor defects in STGD1 also have a cell-autonomous origin, besides the RPE dysfunction. Importantly, we also demonstrated that correcting this pathological phenotype through the modulation of microRNAs 181a and b (miR-181a/b), key regulators of mitochondrial function, ameliorates the STGD1 phenotype. Indeed, genetic inactivation and adeno-associated viral vector-mediated silencing of miR-181a/b in STGD1 models restored OPA1 levels, improved mitochondrial phenotype, and reduced lipofuscin accumulation in the RPE. Our study demonstrates that mitochondrial dysfunction in photoreceptors is an important contributor to STGD1 pathology, opening promising therapeutic avenues for this disorder.

Keywords:  Stargardt disease; miR-181a/b; microRNA; mitochondria; photoreceptors

DOI:  https://doi.org/10.1073/pnas.2504764123
J Cell Biol. 2026 Jun 01. pii: e202507023. [Epub ahead of print]225(6):

Palmitoylation of Tspan4 is essential for migrasome formation.

Shuonan Wang, Weisi Wang, Jiamei Qiao, Sadiq Ali, Zheng Jiang, Dong Jiang, Junjie Ma, Yuwei Huang.

Migrasomes are key organelles in cell-cell communication, playing a role in embryonic morphogenesis, angiogenesis, coagulation, and mitochondrial homeostasis. Migrasome formation involves the assembly of tetraspanin-enriched microdomains (TEMs) into larger macrodomains (TEMAs), but the underlying mechanisms are unclear. Here, we demonstrate that tetraspanin 4 (Tspan4) is highly palmitoylated at six juxtamembrane cysteines. DHHC6 and PPT1 are identified as the main enzymes regulating this modification. Palmitoylation of Tspan4 is critical for Tspan4 clustering and cholesterol recruitment, enabling the TEM to TEMA assembly required for migrasome formation and stabilization. Notably, the palmitoylation-deficient Tspan4 mutant acts in a dominant-negative manner, suppressing migrasome formation not only in cultured cells but also in zebrafish embryos, where it disrupts left-right asymmetry and organ morphogenesis. Collectively, our study establishes protein palmitoylation as a conserved and essential regulator of migrasome assembly, delineating a mechanism whereby Tspan4 palmitoylation drives cholesterol-dependent membrane macrodomain organization to enable migrasome formation and function.

DOI: https://doi.org/10.1083/jcb.202507023
Life Sci Alliance. 2026 Jun;pii: e202603630. [Epub ahead of print]9(6):

Locally synthesized glycyl aminoacyl-tRNA synthetase is important for local translation in neurons.

Tyler Brent de Leon, Adi Golani-Armon, Bar Cohen, Yoav S Arava.

Regulation of gene expression is essential for neuronal development and function. A prominent regulatory mechanism involves synthesis of proteins at their activity site. Such local protein synthesis enables neurons to respond rapidly and tightly to stimuli. Key components of the translation machinery, including mRNA and ribosomes, were identified in subcellular regions of neurons. Yet, the role of tRNAs and their charging enzymes, aminoacyl-tRNA synthetases (ARS), in this process remains largely unclear. Here, we demonstrate that glycyl-tRNA synthetase (Gars1) mRNA is abundant in neurites and undergoes local translation, producing GARS1 protein. Notably, Gars1 mRNA colocalizes with mitochondria in a translation-dependent manner, with its coding sequence (CDS) sufficient to direct this association. The localized GARS1 protein is in close proximity to tRNAGly, and disrupting their proximity impairs local protein synthesis in neurites. These findings establish the functional importance of GARS1 and tRNAGly in neuritic translation and highlight mitochondria as hubs for mRNA transport and translation.

DOI: https://doi.org/10.26508/lsa.202603630
Int J Mol Sci. 2026 Apr 06. pii: 3306. [Epub ahead of print]27(7):

Neurogranin Promotes Neuronal Maturation and Network Activity Through Ca2+/Calmodulin Signaling.

Elena Martínez-Blanco, Raquel de Andrés, Esperanza López-Merino, José A Esteban, Francisco Javier Díez-Guerra.

  Neurogranin (Ng) is a postsynaptic calmodulin-binding protein highly enriched in forebrain neurons and widely implicated in synaptic plasticity. However, whether Ng contributes more broadly to neuronal network maturation and cellular homeostasis remains unclear. Here, we examined the consequences of silencing or restoring Ng to adult physiological levels in primary hippocampal neurons. Ng expression promoted dendritic expansion, increased synaptic number, and shifted the axon initial segment toward the soma, consistent with structural adaptations to enhanced connectivity. Calcium (Ca2+) imaging revealed a marked increase in spontaneous neuronal activity and network synchronization, which was confirmed by electrophysiological recordings showing enhanced burst firing and spike synchrony. At the molecular level, Ng altered Ca2+/calmodulin (CaM) signaling by increasing total CaM levels, reducing Ca2+/CaM-dependent protein kinase II (CaMKII) abundance while increasing its relative autophosphorylation, and downscaling specific ionotropic glutamate receptors. Despite elevated network activity, Ng expression enhanced neuronal metabolic competence and viability, reduced cellular stress signaling and induced modest caspase-3 activation without engagement of apoptotic pathways. Together, these results indicate that Ng promotes neuronal maturation and coordinated network activity while engaging compensatory mechanisms that preserve excitatory balance and neuronal resilience. Our findings identify Ng as a molecular integrator linking Ca2+/CaM signaling with the structural and functional maturation of neuronal networks.

Keywords:  Neurogranin; calcium; calmodulin; neuronal maturation

DOI:  https://doi.org/10.3390/ijms27073306