bims-axbals 2026-04-05 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–04–05
thirty papers selected by
TJ Krzystek

UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.
Lysosomal homeostasis at the crossroads of neurodegeneration.
Pathological microtubule dynamics in Parkinson's disease: Mechanisms and therapeutic implications.
Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets.
Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.
The KIF3B/B/KAP3 tail domain specifically facilitates TRIM46 transport to the axon initial segment.
A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.
Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β-TFEB signaling axis.
Relationship between promyelocytic leukemia protein nuclear bodies and TAR DNA-binding protein-43 aggregation in spinal anterior horn cells in sporadic amyotrophic lateral sclerosis.
ATF3-dependent formation of inclusion bodies in polyQ-expressing human iPSC-derived neurons confers cellular protection.
Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.
Small molecule modulation of organelle membrane contact sites.
The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.
Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.
TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.
Autophagy dysfunction in iPSCs-derived neurons and midbrain organoids carrying a SNCA triplication.
Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion.
Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia.
Three-dimensional organoid screening using a Leica Thunder microscope.
Dysregulation of a novel autophagosome-mitochondria contact contributes to autophagy dysfunction and neurodegeneration in tauopathy.
m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.
Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.
AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.
Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.
Effects of acute fluctuations of extracellular Zinc on network activity of human iPSC-derived neurons; impact of NMDA Receptor and L-Type Calcium Channel Activation.
Cytoskeletal proteins regulates Tau protein in Alzheimer's disease.
Glut1 Acts in Corazonin-Producing Neurons to Regulate Glycogen Storage in Drosophila.
Glycan Markers of Pluripotent Stem Cells.
A Novel Platform for In Vitro Cellular Stretching and Imaging.
AhR inhibition promotes axon regeneration via a stress-growth switch.

Nat Neurosci. 2026 Mar 30.

UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.

Yang Liu, Zhiyuan Huang, Yu-Wen Hsu, Pragney Deme, Ashley M Frankenfield, Suheng Wu, Xiaofeng Zhao, Honghe Liu, Tao Zhang, Elizabeth J Alexander, Mingming Liu, Yanjun Zhang, Haocheng Wang, Yixin Zhou, Mervyn J Monteiro, Ling Hao, Norman J Haughey, Jiou Wang.

Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41593-026-02226-y
J Clin Invest. 2026 Apr 01. pii: e199845. [Epub ahead of print]136(7):

Lysosomal homeostasis at the crossroads of neurodegeneration.

Stefano De Tito, Sharon A Tooze.

Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.

DOI: https://doi.org/10.1172/JCI199845
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00115-4. [Epub ahead of print]150 423-443

Pathological microtubule dynamics in Parkinson's disease: Mechanisms and therapeutic implications.

Kirti Baghel, Ateendra Kumar Dubey, Satyendra Singh, Vijay Kumar Prajapati.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily marked by the degeneration of dopaminergic neurons in the substantia nigra and the pathological accumulation of misfolded α-synuclein in Lewy bodies. This chapter explores the underrecognized role of microtubule (MT) dysregulation in PD pathogenesis, linking disruptions in cytoskeletal integrity to impaired axonal transport and neuronal survival. The fundamental biology of MTs, their dynamics, and their regulation by motor proteins and associated proteins like MT-associated proteins (MAPs), tau, and gamma-tubulin complexes. Special attention is given to how mutations linked to PD, such as those in SNCA (α-synuclein), Parkin, PINK1 (PTEN-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2), lead to MT destabilization, impaired mitophagy, and disruptions in axonal transport. A self-perpetuating cycle of MT disruption and α-synuclein aggregation is proposed, resulting in synaptic failure and dopaminergic neuron loss. The chapter also evaluates emerging therapeutic strategies targeting MT stabilization, including LRRK2 inhibitors, MT-stabilizing agents like Epothilone D, and approaches to modulate α-synuclein aggregation. Challenges such as the blood-brain barrier, off-target effects of MT-targeting drugs, and patient-specific variability in drug response are critically discussed. The future directions include CRISPR-Cas9-based gene therapies and personalized medicine, emphasizing the need for a deeper understanding of PD-related molecular pathways. This comprehensive overview highlights MT dynamics not just as collateral damage but as a central element in PD pathology, offering novel insights into potential avenues for intervention.

Keywords:  Cytoskeletal integrity; Microtubule dysregulation; PINK1-parkin mitophagy pathway; Parkinson’s disease; α-synuclein aggregation

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.019
MedComm (2020). 2026 Apr;7(4): e70689

Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets.

Dong-Yan Song, Lin Yuan, Weiguo Yang, Wen Li, Jia-Yi Li.

  The axon initial segment (AIS) is a specialized neuronal microdomain that serves as a physical diffusion barrier, separating the axon from somatodendritic compartments. As a highly plastic structure, the AIS dynamically regulates neuronal excitability and contributes to circuit homeostasis. Recent advances in super-resolution imaging and disease modeling have expanded our understanding of its role in neurodevelopment and neurodegenerative disorders. This review first systematically outlines the molecular architecture of the AIS, including its cytoskeletal scaffolds and ion-channel complexes. Then, we discuss AIS plasticity, ranging from activity-dependent alterations to the molecular mechanisms that regulate it, and to its key biological functions, such as its role in action potential initiation, neuronal polarization, subcellular organelle sorting, and neural circuit excitability. We further highlight emerging evidence that AIS disruption represents an early pathological event in neurodegenerative and neuropsychiatric disorders. By integrating physiological and pathological perspectives, and by evaluating emerging biomarker strategies and therapeutic interventions, this review outlines directions and challenges for future AIS-targeted therapies. Meanwhile, it summarizes key experimental and potential clinical tools for future AIS research. Overall, elucidating the molecular mechanism of the AIS in both health and disease provides a deeper understanding for advancing the diagnosis and treatment of neurological diseases.

Keywords:  action potential; axon initial segment; neural circuit; neurological disorders; plasticity

DOI:  https://doi.org/10.1002/mco2.70689
PLoS One. 2026 ;21(4): e0346246

Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.

Eleni Christoforidou, Jordan S Rowe, Fabio A Simoes, Raphaelle Cassel, Luc Dupuis, Peter Nigel Leigh, Majid Hafezparast.

Impaired cytoplasmic dynein function has been implicated in amyotrophic lateral sclerosis (ALS) pathogenesis, yet the contributions of spinal interneurons to disease phenotypes remain unclear. We tested the hypothesis that hypomorphic dynein function in cholinergic neurons disrupts the development, survival, or positioning of inhibitory interneuron populations in the lumbar spinal cord. Using ChAT-Cre recombination, we generated four mouse genotypes with graded reductions in dynein activity in ChAT+ cells: Dync1h1+/+ (wildtype), Dync1h1-/+ (hemizygous wildtype), Dync1h1+/Loa (heterozygous Loa mutation), and Dync1h1-/Loa (hemizygous Loa). At 52 weeks of age, lumbar spinal cords (L3-L6) were harvested, cryosectioned, and immunostained for ChAT, GAD-67, Parvalbumin, and Calbindin. Cell counts were performed on confocal images from eight sections per mouse (N = 3 male mice/genotype), and radial distances from the central canal were normalised to gray matter width. Angular distributions were analysed via circular statistics. There were no significant genotype-dependent differences in the numbers of ChAT+, GAD-67+, Parvalbumin+, or Calbindin+ cells, nor in ChAT+ subpopulations (motor neurons versus interneurons) or double-positive interneuron subsets (e.g., ChAT+-GAD-67+, Parvalbumin+-GAD-67+, Parvalbumin+-Calbindin+). Radial positioning relative to the central canal was similarly preserved across all markers and genotypes. Circular-median tests revealed statistically significant shifts in mean angle for ChAT+, GAD-67+, and certain double-positive cells, but these amounted to only 5-10° displacements, translating to lateral shifts of ~10-20 µm, well within single laminar bands, and are unlikely to impact circuit connectivity. Despite substantial motor deficits and hallmark TDP-43 pathology previously seen in these models, impaired dynein function does not precipitate interneuron loss or gross migratory defects in the lumbar spinal cord. Instead, our findings suggest that the primary contributions of dynein to ALS-like phenotypes likely arise from functional disruptions in axonal transport, synaptic maintenance, and neuronal physiology rather than from structural alterations or loss of interneuron populations.

DOI: https://doi.org/10.1371/journal.pone.0346246
J Cell Biol. 2026 May 04. pii: e202503138. [Epub ahead of print]225(5):

The KIF3B/B/KAP3 tail domain specifically facilitates TRIM46 transport to the axon initial segment.

Xuguang Jiang, Sotaro Ichinose, Tadayuki Ogawa, Kento Yonezawa, Nobutaka Shimizu, Nobutaka Hirokawa.

Intracellular transport is essential for neuronal organization, yet how motor proteins achieve cargo selectivity remains incompletely understood. Kinesin-2 motors transport diverse cargos through the heterotrimeric KIF3/KAP3 complex, but whether variations in assembly composition contribute to functional specificity has been unclear. This study provides evidence for heterogeneity in neuronal KIF3/KAP3 assemblies, including a KIF3B-enriched, KAP3-associated population in addition to the canonical KIF3A/B/KAP3 complex. Biochemical and cellular analyses support a preferential association between this KIF3B-enriched assembly and TRIM46, a protein required for axon initial segment organization. Structural analyses further suggest that differences in tail conformation accompany distinct assembly states and may underlie cargo selectivity. Together, these findings support a model in which compositional and structural diversity within kinesin-2 complexes contributes to spatially regulated transport during neuronal development.

DOI: https://doi.org/10.1083/jcb.202503138
Nat Commun. 2026 Mar 31. pii: 2699. [Epub ahead of print]17(1):

A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.

Farzaneh S Mirfakhar, Jacob A Marsh, Chihiro Sato, Kylie J Schache, Miguel A Minaya, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Shannon L Macauley, Celeste M Karch.

Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, and increased undegraded cellular cargo. Pharmacological enhancement of autophagy improves cargo clearance and lowers Tau levels, without restoring defects in lysosomal motility. Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.

DOI: https://doi.org/10.1038/s41467-026-70473-5
Pharmacol Res. 2026 Mar 28. pii: S1043-6618(26)00087-3. [Epub ahead of print]227 108172

Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β-TFEB signaling axis.

Ang Li, Xianglu Xiao, Guopan Liu, Krinos Li, Yixia Ling, Shenglong Deng, Chunzuan Xu, Shu-Qin Cao, Jing Wen, Guang Lu, Guang Yang, Evandro F Fang, Dajiang Qin, Huanxing Su.

  Lysosomal dysfunction is a core pathological driver of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transcription factor EB (TFEB) serves as a master regulator of lysosomal biogenesis, and its pharmacological activation represents a strategy to restore lysosomal function in disease and aging. Here, using a series of artificial intelligence-powered computational virtual screening workflows, we have identified isoginkgetin (ISO), a small-molecule compound, as a potent TFEB activator that promotes mechanistic target of rapamycin complex 1 (mTORC1)-independent TFEB nuclear translocation to enhance lysosomal biogenesis and function. Mechanistically, ISO functions as an ATP-competitive inhibitor that binds to the key Lys85 residue within the ATP-binding pocket of glycogen synthase kinase 3β (GSK-3β), thereby regulating the GSK-3β-TFEB signaling axis to activate TFEB nuclear translocation. Functionally, ISO improves lysosomal function and protects motor neurons differentiated from induced pluripotent stem cells derived from patients with ALS from degeneration. Collectively, these results support the hypothesis that lysosomal dysfunction is a druggable target for ALS.

Keywords:  Amyotrophic lateral sclerosis; Artificial intelligence; GSK-3β–TFEB axis; Isoginkgetin; Lysosome

DOI:  https://doi.org/10.1016/j.phrs.2026.108172
J Neuropathol Exp Neurol. 2026 Apr 02. pii: nlag029. [Epub ahead of print]

Relationship between promyelocytic leukemia protein nuclear bodies and TAR DNA-binding protein-43 aggregation in spinal anterior horn cells in sporadic amyotrophic lateral sclerosis.

Fumiaki Mori, Tomoya Kon, Riho Itazawa, Ami Akatsu, Yasuo Miki, Akira Arai, Hidekachi Kurotaki, Masahiko Tomiyama, Koichi Wakabayashi.

  Promyelocytic leukemia protein nuclear bodies (PML-NBs) and stress granules serve as deposition sites for stress-induced, aggregation-prone proteins. We previously reported that TAR DNA-binding protein 43 (TDP-43) colocalizes with stress granules during early aggregation in sporadic amyotrophic lateral sclerosis (ALS), and recent studies have noted PML-NB loss in familial ALS. To explore the role of PML-NBs in TDP-43 inclusion maturation, we analyzed spinal cord specimens from 12 patients with sporadic ALS and 5 controls using immunostaining for PML and TDP-43. PML-NB counts in anterior horn cells (AHCs) were significantly lower in patients with ALS than in controls (P < 0.05), especially in AHCs with TDP-43 inclusions (P < 0.01). Average numbers of PML-NB decreased progressively with inclusion type (3.1 in diffuse punctate cytoplasmic staining, 2.3 in round inclusions, and 0.8 in skein-like inclusions); all of these were significantly lower than those in inclusion-free AHCs (controls: 4.6; ALS: 5.5; P < 0.01). AHCs in ALS without inclusions showed higher PML-NB counts than in controls (P < 0.05), suggesting an early protective response. In contrast, reduced PML-NBs in mature inclusions may reflect diminished cellular defense. These findings implicate PML-NBs in the pathogenesis of sporadic ALS.

Keywords:  PML; TDP-43 inclusion; anterior horn cell; nuclear body; sporadic amyotrophic lateral sclerosis

DOI:  https://doi.org/10.1093/jnen/nlag029
Cell Death Differ. 2026 Apr 02.

ATF3-dependent formation of inclusion bodies in polyQ-expressing human iPSC-derived neurons confers cellular protection.

Walaa Oweis, Malka Nissim-Rafinia, Elad Dvir, Matan Sorek, Sagiv Shifman, Eran Meshorer.

Huntington's disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation - CAG expansions within the coding region of the Huntingtin (HTT) gene - has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. Here we developed fluorescent iPSC-based human neuronal models for polyQ-related disorders. Comparing cell death in IB+ and IB- iPSC-derived neurons, growing side-by-side, we demonstrate that polyQ IBs have a significant protective effect. Remarkably, knocking out ATF3 prevented polyQ-IB formation and rendered the cells more vulnerable to induced stress. Taken together, our results reveal ATF3's role in polyQ IB formation in human NPCs, and demonstrate that polyQ IBs protect cells from stress-induced death.

DOI: https://doi.org/10.1038/s41418-026-01739-0
Adv Sci (Weinh). 2026 Mar 31. e21101

Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.

Valentina Davi, Pierre Parutto, Yuyi Zhang, Tasuku Konno, Cecile Crapart, Raquel Pereira, John P Franklin, Mosab Ali Awadelkareem, Daniel C Maddison, Michael J Devine, Edgar R Gomes, Joseph Chambers, Elena Koslover, Edward Avezov.

  The endoplasmic reticulum (ER)'s continuous morphology is tightly controlled by ER-shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimer's disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub-Hz firing bursts to ER ultrastructural manipulations in human inducible Pluripotent Stem Cells (hiPSC)-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca2+ bursts. The ER morpho-regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca2+ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca2+-firing cells to ER structural disruptions, rationalizing ER dysfunction in neurodegeneration and unveiling a new role for the continuous ER morphology that could apply universally to Ca2+-firing cells.

Keywords:  calcium oscillations; endoplasmic reticulum Ca2+ refill; endoplasmic reticulum morphology; human iPSC‐derived neurons; modelling; neurodegenerative diseases ; neuronal firing

DOI:  https://doi.org/10.1002/advs.202521101
Trends Pharmacol Sci. 2026 Mar 30. pii: S0165-6147(26)00041-6. [Epub ahead of print]

Small molecule modulation of organelle membrane contact sites.

Minjeong Ko, Jiho You, Eunwoo Cho, Ho Jeong Kwon.

  Organelle membrane contact sites (MCSs) regulate calcium exchange, lipid transfer, metabolism, and cellular stress responses. Dysregulation of MCSs contributes to diverse diseases, yet pharmacological strategies that directly modulate contact architecture remain limited. Recent advances in chemoproteomics and live-cell imaging demonstrate that small molecules can remodel organelle contacts by modulating the conformational states of tethering proteins, coordinating associated effector and regulatory assemblies, and reshaping organelle networks. Here, we propose a pharmacological framework that classifies MCS modulators as stabilizers or destabilizers and review representative compounds, highlighting their molecular mechanisms and emerging therapeutic candidates. We further discuss advanced technologies for visualizing MCS dynamics and identifying small molecule-induced proteoforms. This review positions MCSs as actionable drug targets and outlines future directions for organelle-focused pharmacology.

Keywords:  chemoproteomics; drug discovery; membrane contact sites (MCSs); organelle communication; proteoforms; small molecule modulators

DOI:  https://doi.org/10.1016/j.tips.2026.02.008
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00122-1. [Epub ahead of print]150 397-422

The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.

Chandrabose Selvaraj, Deepali Desai, Elayaperumal Sumitha.

  Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.

Keywords:  Brain; Cytoskeletal proteins; Neurodegenerative diseases; Neuronal degeneration; Neuronal dysfunction

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.026
Int J Biol Macromol. 2026 Mar 28. pii: S0141-8130(26)01645-4. [Epub ahead of print] 151719

Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.

Giulia Di Napoli, Lorenzo Alfurno, Alex Fissore, Eleonora Raccuia, Paolo Olivieri, Mauro Marengo, Simonetta Oliaro-Bosso, Fabrizio Dal Piaz, Gianluca Catucci, Gianfranco Gilardi, Adrian Velazquez-Campoy, Filippo Prischi, Angela De Simone, Francesca Spyrakis, Francesco Di Palma, Salvatore Adinolfi.

  Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, leading to muscle paralysis and respiratory failure. Genetic mutations, notably in the ANXA11 gene, have been implicated in both familial and sporadic ALS forms. ANXA11 functions as a cellular "tether," orchestrating the transport of RNA-protein complexes and lysosomes through its N-terminal (Nt) and C-terminal (Ct) domains, respectively. This study uncovers a novel calcium-dependent regulatory mechanism governing the intramolecular interaction between these domains. Using biochemical, biophysical, and computational approaches, we suggest that in the absence of calcium, ANXA11 adopts a closed conformation with stable Nt-Ct interactions. Elevated calcium levels induce a conformational shift, disrupting this interaction and exposing binding sites for RNA and membranes. Crucially, we show that the ALS-associated D40G mutation in the Nt domain impairs this calcium-regulated interaction, favoring a persistent open conformation that predisposes to toxic protein aggregation. These findings reveal that calcium acts as a molecular switch modulating ANXA11 conformation and function, providing new insights into its role in ALS pathogenesis and potential therapeutic targets.

Keywords:  Amyotrophic lateral sclerosis; Annexin A11; Calcium-regulation; RNA-transport

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151719
Front Mol Neurosci. 2026 ;19 1671909

TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.

Seham Almalki, Mohamed Salama, Matthew J Taylor, Zubair Ahmed, Richard I Tuxworth.

  Mislocalization and aggregation of the DNA/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while TDP-43-depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities.

Keywords:  ALS; ALS-FTD; DDR; DNA damage; DNA repair; FTD; TDP-43

DOI:  https://doi.org/10.3389/fnmol.2026.1671909
NPJ Parkinsons Dis. 2026 Mar 31.

Autophagy dysfunction in iPSCs-derived neurons and midbrain organoids carrying a SNCA triplication.

Catarina Serra-Almeida, Javier Jarazo, Gemma Gomez-Giro, Isabel Rosety, Alise Zagare, Daniele Ferrante, Cláudia Saraiva, Daniela Frangenberg, Jennifer Modamio-Chamarro, Elisa Zuccoli, Ana Clara Cristóvão, Liliana Bernardino, Jens Christian Schwamborn.

Parkinson's disease (PD), characterized by α-Synuclein aggregation and dopaminergic neuronal loss, has no current cure. Autophagy is critical for α-Synuclein clearance, yet its real-time dynamics remain challenging to assess in human-relevant systems. Here, we used live-cell imaging to assess autophagy within human neuronal cultures and midbrain organoids (hMOs) derived from induced pluripotent stem cells (iPSCs) of PD patients carrying a triplication of the α-Synuclein gene (3xSNCA). Using the LC3-Rosella dual-fluorescent reporter, we quantified autolysosomes dynamics in real time. In 3xSNCA neuronal cultures, we detected early autophagy defects. In 3xSNCA hMOs, reduced autolysosome area, increased total and phosphorylated α-Synuclein (pS129), and decreased electrophysiological activity were observed at 50 days of differentiation (DoD). By 70 DoD, autophagy impairment became more pronounced, overlapping with dopaminergic neuron dysfunction. These findings support the use of human iPSCs-derived models to study autophagy dysfunction in PD and demonstrate a temporal correlation between impaired autophagy, α-Synuclein pathology and neuronal degeneration.

DOI: https://doi.org/10.1038/s41531-026-01330-x
Neurochem Int. 2026 Mar 31. pii: S0197-0186(26)00044-6. [Epub ahead of print] 106153

Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion.

Masaru Fujiwara, Ryohei Sakai, Masayuki Takahashi, Gen Matsumoto, Tadafumi Hashimoto, Tomohiro Kabuta.

  Mutations in components of the endosomal sorting complex required for transport (ESCRT)-III, such as CHMP2B and VPS4A/B, are known to cause neurological disorders, including frontotemporal lobar degeneration (FTLD) and developmental encephalopathies. Although ESCRT complexes are required for macroautophagy and for certain forms of microautophagy, the effects of ESCRT-III dysfunction on intracellular protein degradation remain unclear. In this study, we investigated how ESCRT-III dysfunction affects intracellular protein clearance using multiple genetic manipulations, including a dominant-negative form of VPS4 and an FTLD-associated CHMP2B mutant. We found that despite marked suppression of macroautophagic flux, inhibition of ESCRT-III promoted protein clearance in multiple cell types, including Neuro2a cells. Such clearance was also observed in ATG13- or ATG5-knockout cells, confirming that this process occurs independently of macroautophagy. Imaging revealed increased punctate accumulation of substrate proteins in lysosomes, suggesting the activation of a microautophagy-like pathway independent of ESCRT-III. In addition, ESCRT-III inhibition enhances extracellular vesicle-independent protein secretion. Cell-to-cell transmission of aggregated tau, assessed using conditioned medium, was also promoted by ESCRT-III inhibition. These findings suggested that ESCRT-III dysfunction, while impairing canonical autophagy, paradoxically activates alternative degradation and secretion pathways that may contribute to the pathogenesis of neurological disorders.

Keywords:  ESCRT; autophagy; lysosome; microautophagy; neurodegenerative disorder

DOI:  https://doi.org/10.1016/j.neuint.2026.106153
bioRxiv. 2026 Mar 27. pii: 2026.03.25.713523. [Epub ahead of print]

Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia.

Yi Zeng, Jian Xiong, Anastasiia Lovchykova, Thao Phuong Nguyen, Abigail Song, Semma W Gitler, Monther Abu-Remaileh, Aaron D Gitler.

Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer disease. Mutations in GRN , which encodes progranulin, are a major cause of FTD. Common genetic variants in the TMEM106B gene modify risk of FTD and the effect is especially strong in GRN mutation carriers. Intriguingly, in GRN mutation carriers, being homozygous for the protective TMEM106B haplotype seems to confer near lifetime protection against FTD. Despite the strong genetic link between GRN and TMEM106B , how these two genes interact mechanistically has remained unresolved. Recent studies have revealed that a C-terminal fragment of TMEM106B forms amyloid fibrils and accumulates in the brains of older individuals and patients with neurodegenerative disorders, including FTD. How the production of this fragment connects to granulin deficiency is also unknown. Using lysosome immunoprecipitation, we show that granulin deficiency drives the accumulation of the TMEM106B C-terminal fragment within lysosomes in Grn -knockout mice and GRN -null human iPSC-derived neurons. Recombinant progranulin supplementation reduced TMEM106B C-terminal fragment accumulation. Isogenic neurons carrying the TMEM106B risk allele displayed allele-dose-dependent fragment accumulation that was reversible by progranulin. Structural and genetic analyses demonstrated that TMEM106B dimerization stabilizes the protein and limits C-terminal fragment formation. These findings define a lysosomal pathway linking granulin deficiency to TMEM106B C-terminal fragment accumulation and explain how protective TMEM106B alleles can confer resistance to FTD, even for GRN mutation carriers.
One Sentence Summary: Granulin deficiency drives lysosomal accumulation of an amyloidogenic TMEM106B C-terminal fragment, revealing a molecular mechanism that explains how TMEM106B alleles can confer risk or protection from frontotemporal dementia.

DOI: https://doi.org/10.64898/2026.03.25.713523
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00195-5. [Epub ahead of print]204 205-236

Three-dimensional organoid screening using a Leica Thunder microscope.

Tudor Manoliu, Benoît Maury.

  3D organoids are vital for biomedical research, offering complex tissue models superior to 2D cultures for studying development, disease, and drug responses. High-throughput imaging of these structures is challenging. This report details a method for screening 3D organoids using the Leica Thunder microscope, featuring Computational Clearing for enhanced deep imaging. The protocol covers sample preparation, optimized image acquisition using LAS X, and analysis with FiJi/ImageJ for quantification. Applications include drug discovery and disease modeling. The Leica Thunder facilitates efficient 3D organoid screening.

Keywords:  3D culture; Drug discovery; High content screening; High-throughput; Leica Thunder; Organoids; Patient-derived organoids; Spheroids

DOI:  https://doi.org/10.1016/bs.mcb.2025.09.007
bioRxiv. 2026 Mar 25. pii: 2026.03.23.713823. [Epub ahead of print]

Dysregulation of a novel autophagosome-mitochondria contact 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 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 new class of mitochondria-organelle communication: autophagosome/autophagic vacuole (AV)-mitochondria (Mito) contact, which exhibits hyper-tethering 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 AMP-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 new insights into AV-Mito contact dysregulation in tauopathy-related autophagy failure, laying the groundwork for the development of potential therapeutics to combat tauopathy diseases.

DOI: https://doi.org/10.64898/2026.03.23.713823
Mol Brain. 2026 Mar 29.

m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.

Xuehua Zhou, Peiyang Yu, Xia Shen.

  m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its spatial organization across neurons and glial cells, highlighting established roles in brain development, synapse formation, and axon growth. We then focus on experience-dependent plasticity, synthesizing evidence that neuronal activity and environmental inputs dynamically reshape m6A to regulate immediate-early transcription and local translation at synapses across sensory, cognitive, emotional, and motor domains. With aging, m6A programs are reconfigured in a cell-type-specific manner, a shift associated with reduced plasticity and increased vulnerability. We further survey disease-associated alterations in m6A across Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke-related cognitive impairment, ALS and FTD, as well as metal or toxin exposure, emphasizing convergent effects on dopaminergic and glutamatergic signaling, synaptic integrity, inflammation, and cellular stress responses. Finally, we discuss emerging opportunities and conceptual challenges in targeting m6A enzymes or reader proteins, and outline priorities for future work, including cell-type- and subcellular-resolved mapping, causal perturbation in defined circuits and life stages, and the development of biomarkers and selective modulators. Together, these observations position m6A as a molecular interface linking experience-dependent plasticity, brain aging, and neurodegenerative vulnerability.

Keywords:  Aging; Experience-dependent plasticity; Neural development; Neurodegenerative diseases; m6A RNA methylation

DOI:  https://doi.org/10.1186/s13041-026-01297-z
Commun Biol. 2026 Mar 31.

Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.

Hanlan Yin, Zhichao Ren, Yan Zhang, Yuxiang Wang, Yiyang Sun, Xueqi Fu, Wenfu Yan, Fuqiang Zhang, Linlin Zeng.

Amyotrophic lateral sclerosis (ALS) involves disrupted lipid metabolism. Bax inhibitor 1 (BI1), an endoplasmic reticulum protein downregulated in ALS neuroprotective, represents a therapeutic target, but its metabolic regulatory mechanisms are incompletely understood. Using transcriptomics in skeletal muscle of ALS mice pre- and post-BI1 treatment, we identified BI1-regulated pathways. Structure-based virtual screening of FDA-approved compounds nominated lisinopril as a BI1 activator. Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and protecting against SOD1G93A-induced apoptosis in NSC34 cells. Concurrently, it regulated TGF-β1/mTOR-dependent autophagy, maintained NMJ integrity, and reshaped triglyceride/sphingolipid/glycerophospholipid metabolism to attenuate spinal cord pathology in ALS mice, promoting energy metabolism shift toward glucose oxidation. Additionally, lisinopril inhibited the TGF-β1/Smad2/3 pathway to alleviate muscle fibrosis, downregulate Acp5/FN expression, and reduce type I collagen deposition. In conclusion, this study provides evidence that pharmacological activation of BI1 by lisinopril suppresses TGF-β1, modulates lipid metabolism, and ameliorates ALS pathology, demonstrating promising therapeutic repurposing potential.

DOI: https://doi.org/10.1038/s42003-026-09930-2
CNS Neurol Disord Drug Targets. 2026 Mar 25.

AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.

N Pavithra, Rukaiah Fatma Begum, S Thanga Ashwini, S Nirenjen, Anuragh Singh, M Manisha, S Sridevi, S Ankul Singh.

   INTRODUCTION/OBJECTIVE: Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are examples of neurodegenerative disorders (NDDs) that share overlapping neuropathological processes and largely affect motor coordination. For early diagnosis, illness monitoring, and treatment targeting, it is essential to find trustworthy biomarkers that represent motor circuit dysfunction. The purpose of this study is to summarize the state of the art regarding molecular, neurochemical, and imaging biomarkers that are pertinent to motor impairment and to investigate the function of artificial intelligence (AI) in their identification and verification Methods: With an emphasis on biomarker discovery, validation, and AI/ML applications in PD, HD, ALS, and SCAs, a thorough literature search was carried out in the PubMed, Scopus, and Google Scholar databases for research published between 2015 and 2025. The motor-specific correlations of key molecular (α-synuclein, tau, neurofilament light chain, TDP-43, mutant huntingtin), neuroimaging, and digital biomarkers were carefully examined Results: AI-driven methods, such as deep learning and machine learning, have shown great promise in combining multimodal data from digital, fluid, and imaging sources. These techniques enhanced the detection of disease-specific biomarker signatures, especially those associated with deficiencies in motor coordination Discussion: Data heterogeneity, biomarker standardization, model interpretability, and limited cross-disease validation are still issues despite encouraging developments. Improving the clinical reliability of AI-based biomarker models requires filling in these gaps Conclusion: An effective foundation for deciphering intricate motor neurological pathways is provided by AI-assisted biomarker discovery. Transparent algorithms, multicenter data integration, and ethical frameworks should be given top priority in future research to guarantee clinical translation and better patient stratification.

Keywords:  Neurodegenerative illnesses; biomarkers for imaging; biomarkers in molecules; coordination of movement; wearable sensors.

DOI:  https://doi.org/10.2174/0118715273436955260126215111
bioRxiv. 2026 Mar 27. pii: 2026.03.24.712448. [Epub ahead of print]

Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.

Joyce Yang, Mitsunori Nomura, Jonathan X Meng, Thelma Y Garcia, Timothy R Matsuura, Daniel P Kelly, Ken Nakamura, John C Newman.

Glucose is the brain's primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimer's disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival-even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimer's disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimer's.

DOI: https://doi.org/10.64898/2026.03.24.712448
Neuropharmacology. 2026 Mar 27. pii: S0028-3908(26)00125-5. [Epub ahead of print]292 110952

Effects of acute fluctuations of extracellular Zinc on network activity of human iPSC-derived neurons; impact of NMDA Receptor and L-Type Calcium Channel Activation.

Mouhamed Alsaqati, Josephine E Haddon, Jeremy Hall, Adrian J Harwood, Lawrence S Wilkinson.

   BACKGROUND AND PURPOSE: Zinc is an essential trace element involved in numerous biological processes including in the central nervous system. Strong genetic evidence has implicated dysregulation of free Zn2+ levels in the pathophysiology of schizophrenia and there is evidence for its involvement in other psychiatric and neurological disorders. This study aimed to investigate the effects of fluctuations in extracellular Zn2+ levels on human neuronal function to better understand possible pathophysiological mechanisms.
EXPERIMENTAL APPROACH: Using multi-electrode array (MEA) methods, we examined the effects of manipulating extracellular Zn2+ on intrinsic neuronal function and coordinated neuronal network activity in human induced pluripotent stem cell-derived neurons. We confirmed effects were related to extracellular free Zn2+ ions using the specific membrane-impermeable chelator ZX1. We then manipulated NMDA receptors (NMDARs) and L-type calcium channels (LTCCs) with drug compounds and assessed gene expression with qPCR to probe molecular mechanisms of Zn2+ effects.
KEY RESULTS: Extracellular Zn2+affected network activity in a dose-dependent manner. Addition of nMolar concentrations of ZnCl2 within the physiological range had specific effects on neuronal synchrony that were reversible by chelation of free Zn2+ and by NMDAR or LTCC activation. Following addition of higher, μMolar, concentrations of ZnCl2 the effects of Zn2+ were associated with impaired intrinsic neuronal excitability, irreversible network dysfunction that was resistant to NMDAR or LTCC activation and upregulation of the apoptosis cell death marker cleaved caspase-3.
CONCLUSIONS AND IMPLICATIONS: Acute fluctuations in extracellular Zn2+can impact both phasic neuronal connectivity and at higher levels can lead to neuronal toxicity in human neurons. The data may have relevance for, and explain in part, the known links between Zn2+ and conditions such as schizophrenia, where the malfunctioning synapse is increasingly the focus of pathology, and neurological conditions associated with neurotoxicity.

Keywords:  Extracellular zinc; Human neurons; L-type calcium channels; Multi-electrode arrays; NMDARs

DOI:  https://doi.org/10.1016/j.neuropharm.2026.110952
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00125-7. [Epub ahead of print]150 1-28

Cytoskeletal proteins regulates Tau protein in Alzheimer's disease.

Subashchandrabose Chinnathambi, Anusree Adityan.

  Cytoskeletal proteins, particularly microtubules and actin, play critical roles in maintaining neuronal structure, transport, and function. In Alzheimer's disease (AD), the Tau protein, which normally stabilizes microtubules, becomes hyperphosphorylated and forms neurofibrillary tangles, leading to Tauopathies. This pathological change disrupts microtubule dynamics, axonal transport, and overall neuronal integrity. The cytoskeletal proteins like actin, tubulin, MAPs, ankyrin, gelsolin, vimentin, drebrin, septins, cofilin, spectrin, intermediate filaments and Tau role and function in Alzheimer's disease. Cross-talk between microtubules and actin further exacerbates Tau pathology, contributing to synaptic dysfunction, oxidative stress, and neuronal degeneration and dysregulation accelerates neurodegenerative processes, and Tauopathies. Tau pathology impairs synaptic plasticity by disrupting both actin and microtubule cytoskeletons, leading to dendritic spine loss, synaptic failure, and memory impairment. Compounds that prevent tau hyperphosphorylation or promote its dephosphorylation (e.g., GSK-3β inhibitors) may help stabilize microtubules. Cytoskeletal dysfunction is associated with oxidative stress. Compounds that reduce oxidative stress could protect the cytoskeleton from further damage. Since inflammation exacerbates tau pathology and cytoskeletal breakdown, targeting neuroinflammation may have protective effects on cytoskeletal integrity.

Keywords:  Actin regulation; Alzheimer’s disease; Cytoskeletal proteins; Intermediate filaments regulation; Microtubule dynamics; Tauopathy

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.029
Front Biosci (Schol Ed). 2026 Mar 19. 18(1): 47458

Glut1 Acts in Corazonin-Producing Neurons to Regulate Glycogen Storage in Drosophila.

Prem Patel, Justin R DiAngelo.

   BACKGROUND: Metabolic homeostasis is regulated by numerous genes, whose dysregulation leads to metabolic diseases such as obesity and diabetes. Several genes important for lipid storage were identified in a buoyancy-based screen in Drosophila larvae, including Glucose transporter 1 (Glut1), which encodes a glucose uniporter. Previous studies have identified metabolic functions of Glut1 in the whole fly brain; however, the specific neurons in which Glut1 acts to regulate nutrient storage remain unknown.
METHODS: To determine the neuronal populations in which Glut1 regulates lipid and carbohydrate storage, Glut1 levels were decreased in specific neurons, and triglycerides (TAGs) and glycogen levels were measured. We specifically decreased Glut1 expression in corazonin (Crz)-expressing neurons, a neuronal population that expresses the corazonin gene (Crz), which encodes a neuropeptide involved in carbohydrate metabolism.
RESULTS: Targeting RNAi against Glut1 in Crz neurons reduced glycogen levels in males but did not alter TAG levels. To further characterize this nutrient storage phenotype, we measured the expression of two genes involved in glycogen storage, glycogen phosphorylase (Glyp) and glycogen synthase (Glys) as well as the Crz transcript. Notably, knocking down Glut1 in Crz-expressing neurons increased Glys and Crz transcript levels.
CONCLUSIONS: These data suggest that Glut1 acts in the Crz-expressing neurons to regulate Crz levels and organismal glycogen metabolism.

Keywords:   Drosophila ; carbohydrate metabolism; corazonin (Crz); glycogen; glycogen phosphorylase; glycogen synthase; neuropeptides

DOI:  https://doi.org/10.31083/FBS47458
Adv Exp Med Biol. 2026 ;1491 283-294

Glycan Markers of Pluripotent Stem Cells.

Tomoko Watanabe, Hiroaki Tateno.

  Pluripotent stem cells (PSCs) are a unique population of cells, capable of infinite self-renewal and differentiation into many cell types, making them essential for regenerative medicine, tissue engineering, and drug discovery. With the increasing use of PSCs in clinical trials, it is crucial to accurately assess their differentiation status and understand the diversity within PSC populations. Glycan markers have emerged as key tools for evaluating the undifferentiated state of PSCs, as well as for live and fixed imaging, and for isolating particular cell populations by applying approaches such as fluorescence-activated cell sorting (FACS). This article summarizes the glycan markers used to assess the undifferentiated states of both mouse and human PSCs, which include embryonal carcinoma cells (ECCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). By offering a summary of these markers, we aim to advance our understanding of their role in PSC biology, facilitating further developments in stem cell research and broadening medical applications.

Keywords:  Antibody; Embryonic carcinoma cell; Embryonic stem cell; Glycan antigen; Glycan marker; Induced pluripotent stem cell; Lectin; Pluripotent stem cell

DOI:  https://doi.org/10.1007/978-3-032-04153-1_18
J Vis Exp. 2026 03 10.

A Novel Platform for In Vitro Cellular Stretching and Imaging.

Benjamin M Goykadosh, Suzanne E Stasiak, Vasuretha Chandar, Samuel R Polio, Harikrishnan Parameswaran.

Cells respond to mechanical cues from their environment, such as changes in extracellular matrix (ECM) stiffness and cyclic strain, which regulate cellular processes including cell fate determination, intercellular communication, and development. Alterations in these forces contribute to or drive disease progression in conditions like asthma, hypertension, and cancer. While existing in-vitro stretching devices can impose uniaxial or isotropic strains, they often use non-physiological stiffnesses, limit live imaging, or cannot achieve high strain amplitudes relevant to physiological and pathological conditions. Here, we present a compact, microscope-compatible stretcher device that applies controlled isotropic or uniaxial strain to adherent cells on elastomeric culture dishes. These dishes feature a tunable Young's modulus and are compatible with a variety of matrix protein coatings for cell adhesion, allowing independent modulation of substrate stiffness and ECM composition. Importantly, the device's ease of operation is facilitated by its stepper motor-driven design, which supports the generation of programmable cyclic waveforms. We demonstrate the device's capability by quantifying intracellular calcium dynamics and cell traction forces in primary human airway smooth muscle cells under mechanical stretch. This platform provides a versatile tool for investigating the effect of mechanical cues on cellular function in both healthy and disease-relevant contexts.

DOI: https://doi.org/10.3791/69779
Nature. 2026 Apr 01.

AhR inhibition promotes axon regeneration via a stress-growth switch.

Dalia Halawani, Yiqun Wang, Jiaxi Li, Daniel Halperin, Haofei Ni, Molly Estill, Aarthi Ramakrishnan, Li Shen, Arthur Sefiani, Cédric G Geoffroy, Roland H Friedel, Hongyan Zou.

Axon regeneration is limited in the mammalian central nervous system1. Neurons must balance stress responses with regenerative demands after axonal injury2, but the mechanisms remain unclear. Here we identify aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix/PER-ARNT-SIM (bHLH-PAS) transcription factor, as a key regulator of this stress-growth switch. We show that ligand-mediated AhR signalling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models. Mechanistic studies reveal that axotomy-induced AhR activation in dorsal root ganglion neurons enforces proteostasis and stress-response programs to preserve tissue integrity. By contrast, AhR ablation redirects the neuronal response towards elevated de novo translation and pro-growth signalling, enabling axon regeneration. This growth-promoting effect requires HIF1α, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response and DNA hydroxymethylation to rewire neuronal injury-response programs. Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis and metabolic signalling to control the balance between stress adaptation and axonal repair.

DOI: https://doi.org/10.1038/s41586-026-10295-z