bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2026–07–19
seventeen papers selected by
TJ Krzystek
  1. Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration.
  2. Role of ESCRT pathway and autophagy in neurodegenerative diseases.
  3. Endogenous βⅢ-Tubulin FRAP Reveals microtubule dynamics in living developing neurons.
  4. Reducing PI4KIIIα Levels or Activity Limits Tau Seed Internalization and Assembly in Human Cortical Neurons.
  5. Human Platelet-Derived Extracellular Vesicles Are Internalized by Human Induced Pluripotent Stem Cell-Derived Neurons Under Control and Hypoxic Conditions.
  6. Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.
  7. HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A.
  8. Sensitive detection of lysosomal membrane permeabilization using the galectin puncta assay.
  9. Clearance and secretion of α-synuclein by RTN3L-mediated endoplasmic reticulum autophagy.
  10. Spatial confinement shapes organelle architecture and remodeling in axons.
  11. Damage control: new functions for the Arp2/3 complex and WHAMM in autophagy and lysosomal homeostasis.
  12. Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.
  13. Volume electron microscopy in axon regeneration research: insights into mitochondria, endoplasmic reticulum, and membrane contacts.
  14. Plasma Proteomic Changes in GRN and C9orf72 Frontotemporal Dementia.
  15. Understanding the cellular architecture of Huntington's disease.
  16. Targeting DNA mismatch repair in Huntington's disease.
  17. Label-free segmentation of mitochondria for simultaneous morphological and metabolic studies.
  1. bioRxiv. 2026 Jun 24. pii: 2026.06.23.733857. [Epub ahead of print]
    Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration.
    Stephanie L Sarbanes, Jakub Ziak, Alex L Kolodkin, Antonina Roll-Mecak.
      Microtubule dynamics regulation is critical for neuronal development, yet how neurons regulate tubulin levels remains poorly understood. Tetratricopeptide repeat domain 5 (TTC5) mediates the co-translational degradation of tubulin transcripts in response to excess soluble tubulin, a.k.a. "tubulin autoregulation", and TTC5 mutations are associated with cerebral atrophy, speech and motor impairment. Despite clinical relevance, the role of TTC5 and tubulin autoregulation in neurons has not been established. Using human induced pluripotent stem cells (iPSCs)-derived cortical-like neurons, we demonstrate that tubulin autoregulation is active in neurons and fully TTC5-dependent. Loss of TTC5 function suppresses microtubule polymerization and impairs axonal outgrowth and arborization, while enhancing cellular motility. These phenotypes recapitulate in vivo where TTC5 loss in mouse cerebral cortex projection neurons disrupts axon and dendrite arborization and drives aberrant hypermigration. Patient disease mutants phenocopy this motility dysregulation, directly linking TTC5 dysfunction to clinically relevant neurological deficits. Together, our findings establish tubulin autoregulation and its mediators as essential regulators of neuronal morphogenesis and connectivity and provides a mechanistic framework for understanding TTC5-associated neurodevelopmental disease.
    DOI:  https://doi.org/10.64898/2026.06.23.733857
  2. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00052-8. [Epub ahead of print]187 1-16
    Role of ESCRT pathway and autophagy in neurodegenerative diseases.
    Shweta Dongre, Naveen Soni, Bhawana Bissa.
      Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Autophagy; ESCRT; MVB; Neurodegeneration; Parkinson’s disease
    DOI:  https://doi.org/10.1016/bs.irn.2026.05.022
  3. Neurosci Res. 2026 Jul 16. pii: S0168-0102(26)00079-9. [Epub ahead of print] 105092
    Endogenous βⅢ-Tubulin FRAP Reveals microtubule dynamics in living developing neurons.
    Yuri Sakai, Yuki Ogawa, Hiroaki Misonou.
      Microtubules support neuronal morphology, intracellular transport, and neurite growth, but how microtubule turnover is regulated across neuronal compartments remains incompletely understood. To examine microtubule dynamics under physiological expression conditions, we expressed EGFP-tagged βIII-tubulin from the endogenous Tubb3 locus in cultured rat hippocampal neurons and measured tubulin turnover using fluorescence recovery after photobleaching (FRAP). FRAP analysis revealed pronounced spatial differences in microtubule dynamics at 9 days in vitro (DIV), with the highest turnover observed in growth cones and substantially slower turnover in dendrites, axons, and the axon initial segment (AIS). Microtubule turnover further decreased between 9 and 17 DIV in dendrites and axons, indicating progressive stabilization during neuronal maturation, whereas turnover in the AIS remained largely unchanged. Analysis of EB3 comet dynamics suggested that microtubule polymerization contributes substantially to tubulin turnover. In addition, manipulation of the dendritic microtubule-associated protein MAP-2 altered tubulin FRAP, indicating that MAP-2 contributes to the regulation of neuronal microtubule dynamics. Together, these results demonstrate that microtubule turnover is spatially and developmentally regulated in neurons.
    Keywords:  Culture neurons; FRAP; Knock-in; Neuronal development
    DOI:  https://doi.org/10.1016/j.neures.2026.105092
  4. Cells. 2026 Jul 07. pii: 1228. [Epub ahead of print]15(13):
    Reducing PI4KIIIα Levels or Activity Limits Tau Seed Internalization and Assembly in Human Cortical Neurons.
    Eleonora Clemente, Ramakrishnan Sivasubramanian, Susanne Kordes, Priyanka Bhatia, Ruth Hans, Stefanie Vogel, Matthias Baumann, Bert Klebl, Jared Sterneckert.
      Tau protein aggregation and spreading are central features of neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. Here, we investigated the role of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) in regulating tau propagation. We first used tau biosensor cells to demonstrate that both pharmacological inhibition and genetic reduction in PI4KIIIα effectively reduce the seeding of tau aggregation by extracellular seeds. To extend these findings to a more physiologically relevant system, we generated induced pluripotent stem (iPS) cell-derived cortical neurons carrying pathogenic MAPT mutations. These neurons rapidly acquired tauopathy-associated features, including expression of disease-relevant isoforms such as 4R tau, thereby enabling in vitro modeling of tau pathology. Using this model, we established phenotypic assays to monitor tau propagation and aggregation and applied them to test candidate small molecules. Notably, inhibition of PI4KIIIα consistently reduced seeding of tau assemblies in human neurons, highlighting this kinase as an important player in the seeding of tau pathology. Collectively, our work identifies PI4KIIIα as a regulator of tau pathology and provides new experimental platforms to dissect the molecular mechanisms of tau propagation. These findings open potential avenues for the development of strategies to slow or prevent tau-mediated neurodegeneration in the central nervous system.
    Keywords:  PI4KA; PI4KIIIα; disease modeling; iPS cells; induced pluripotent stem cells; prion-like spreading; tau; tauopathy
    DOI:  https://doi.org/10.3390/cells15131228
  5. J Extracell Biol. 2026 Jul;5(7): e70168
    Human Platelet-Derived Extracellular Vesicles Are Internalized by Human Induced Pluripotent Stem Cell-Derived Neurons Under Control and Hypoxic Conditions.
    Venla Harju, Kai Härkönen, Ulla Impola, Saara Laitinen, Susanna Narkilahti.
      Ischaemic brain stroke is among the leading causes of death and disability worldwide. However, the current treatments have a limited time window and regeneration potential. Clinically relevant human platelet-derived extracellular vesicles (EVs) offer potential neuroprotective treatment for stroke. Here, the neuronal uptake of carboxyfluorescein succinimidyl ester (CFSE)-labelled EVs was confirmed by confocal imaging and three-dimensional (3D) image analysis with Imaris software. The results showed that human induced pluripotent stem cell (hiPSC)-derived neurons can internalize EVs. We also show the colocalization of EVs with cellular organelles: early endosomes and lysosomes. We used an in vitro human model of stroke to study the effects of hypoxia on neurons. After hypoxia, the activity of the neurons, including spiking and bursting, decreased. However, the activity was restored after 72 h of reperfusion. EVs did not affect neuronal activity acutely, but during long-term follow-up, neurons showed increased activity. Together, our findings provide insights into the effects of platelet-derived EVs on neuronal uptake, morphology and functionality and changes after hypoxic insult in an in vitro human model.
    Keywords:  acute stroke; extracellular vesicles; hypoxia; in vitro; microelectrode array; neuron
    DOI:  https://doi.org/10.1002/jex2.70168
  6. Acta Neuropathol Commun. 2026 Jul 11.
    Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.
    Jenna M Gregory.
      
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Clinical trials; Neuron-derived extracellular vesicles; Neuropathology; Pharmacodynamic biomarkers; Surrogate endpoints; TDP-43
    DOI:  https://doi.org/10.1186/s40478-026-02376-x
  7. JCI Insight. 2026 Jul 14. pii: e200106. [Epub ahead of print]
    HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A.
    Lydia H Jestice, Larissa Butler, Rebecca A Lea, Kathryn I Adamson, Jonas Van Lent, Stuart L Johnson, Hollie Weedon, Eldriena D'Silva, Gabriele Gelezauskaite, Bob Asselbergh, Eloise Brown, Owen Laing, Christopher J Price, Dylan Stavish, Anestis Tsakiridis, Mark O Collins, Vincent Timmerman, Kurt J De Vos, Alison E Twelvetrees, Andrew J Grierson, Ivana Barbaric.
      Charcot-Marie-Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.
    Keywords:  Cell biology; Neuromuscular disease; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.200106
  8. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00123-8. [Epub ahead of print]209 27-40
    Sensitive detection of lysosomal membrane permeabilization using the galectin puncta assay.
    Konstantinos Danias, Victoria Alexandra Bjerregaard, Marja Jäättelä.
      The Lysosomal Galectin Puncta Assay is a microscopy-based technique able to detect even minor lysosomal leakage with high sensitivity. This protocol describes the detection of galectin puncta as markers of lysosomal membrane permeabilization, a process that relies on the high-affinity binding of the cytosolic galectins to the luminal glycans exposed on damaged lysosomes. Compared to traditional methods, the Galectin Puncta Assay offers high sensitivity, detects subtle lysosomal leakage, and enables analysis at single-lysosome level. Here, we provide a step-by-step protocol for this assay, covering sample preparation, immunostaining, imaging and image quantification.
    Keywords:  Galectin puncta; Lysosomal leakage; Lysosomal membrane permeabilization
    DOI:  https://doi.org/10.1016/bs.mcb.2026.04.002
  9. Mol Biol Cell. 2026 Jul 15. mbcE26030138
    Clearance and secretion of α-synuclein by RTN3L-mediated endoplasmic reticulum autophagy.
    Yihong Ye, Kamal Kumar, Yue Xu, Fenfen Xu, Susan Ferro-Novick.
      The misfolding and aggregation of α-synuclein (α-syn), an abundant synaptic protein, leads to the pathogenesis of Parkinson's disease and related synucleinopathies. The cell-to-cell propagation of seeding-competent α-syn is initiated by unconventional protein secretion, yet the physiological pathway(s) underlying this process remain poorly defined. Here we show that α-syn secretion in human cells is mediated by Reticulon-3L (RTN3L)-dependent endoplasmic reticulum autophagy (ER-phagy), a conserved protein quality-control pathway that safeguards ER protein homeostasis. We also demonstrate that RTN3L cooperates with several autophagy regulators, including the ULK1 cofactor FIP200, to drive the delivery of α-syn into an acidic endolysosomal compartment. Increasing concentrations of α-syn disrupt ER-lysosome traffic and α-syn-containing vesicles appear to be rerouted to the cell surface. Consistent with this proposal, knockdown of vesicle associated SNAREs, that mediate fusion at the cell surface, disrupt α-syn secretion. These findings suggest that pathogenic α-syn secretion arises as a by-product of a physiological clearance mechanism, driven by the fusion of autophagosome-derived vesicles with the plasma membrane. Our results provide a conceptual framework for understanding how an intracellular proteostasis pathway, when mis-regulated, could contribute to the spread of neurodegenerative pathology.
    DOI:  https://doi.org/10.1091/mbc.E26-03-0138
  10. bioRxiv. 2026 Jul 11. pii: 2026.07.07.737043. [Epub ahead of print]
    Spatial confinement shapes organelle architecture and remodeling in axons.
    Mihir Relan, Venkata Mallampalli, Benjamin A Barad, Andrea K H Stavoe, M Neal Waxham.
      Axons are extended cellular compartments that mediate neuronal connectivity over extraordinary distances, placing unique demands on local organelle organization and trafficking. How these geometric constraints influence organelle architecture remains poorly understood. Here, we used cryo-electron tomography and quantitative morphometric analyses to define the three-dimensional ultrastructural organization of dorsal root ganglion axons in a near-native state. We identify distinct vesicle populations with tightly versus broadly constrained size distributions and reveal a continuum of endolysosomal and autophagic intermediates that highlight the dynamic nature of membrane remodeling in growing axons. Unexpectedly, we observe vesicular structures enclosed within the lumen of the endoplasmic reticulum, suggesting a previously undescribed mechanism of ER membrane remodeling. Across multiple organelle classes, morphology and size are constrained by axonal geometry. This principle is most evident in mitochondria, which undergo dramatic narrowing and remodeling at varicosity - axon boundaries to traverse confined axonal segments. Together, these findings reveal spatial confinement as a fundamental organizing principle of axonal cell biology.
    SUMMARY: Cryo-electron tomography establishes a quantitative framework for organelle organization in axons. Diverse membrane trafficking pathways, including endolysosomal intermediates and mitochondria, exhibit structural adaptations to axonal geometry, identifying spatial confinement as a fundamental organizing principle of axonal cell biology.
    DOI:  https://doi.org/10.64898/2026.07.07.737043
  11. Autophagy Rep. 2026 ;5(1): 2698348
    Damage control: new functions for the Arp2/3 complex and WHAMM in autophagy and lysosomal homeostasis.
    Lianna H Wagner, Kenneth G Campellone.
      Macroautophagy is an intracellular degradation process that relies on autophagosomes and lysosomes to maintain cellular and organismal homeostasis. Actin cytoskeletal rearrangements driven by the Arp2/3 (actin-related protein 2/3) complex, an essential actin nucleator, impact multiple steps of this pathway, but where and when Arp2/3-mediated actin assembly is most influential has remained unclear. Recent work now shows that the Arp2/3 complex is crucial in the later stages of autophagy due to its function in maintaining lysosomal integrity. WHAMM (WASP homolog associated with actin, membranes, and microtubules) is the key nucleation-promoting factor that activates Arp2/3 at permeabilized lysosomes, uncovering new roles for actin, the Arp2/3 complex, and WHAMM in lysosomal damage responses.
    Keywords:  ATG8; Actin; Arp2/3 complex; JMY; LC3; WASP; WHAMM; autophagy; cytoskeleton; lysosome
    DOI:  https://doi.org/10.1080/27694127.2026.2698348
  12. Cell Commun Signal. 2026 Jul 15.
    Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.
    Myungjin Jo, Seyeon Kim, Junghwa Woo, Jin-Sung Park, Seung Hyun Kim, Minyeop Nahm, Sang Ryong Kim, Shinrye Lee, Hyung-Jun Kim.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD.
    METHODS: The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-κB) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS.
    RESULTS: DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-κB-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE.
    CONCLUSION: DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.
    Keywords:  Amyotrophic lateral sclerosis; Astrocytes; Chemokines; Frontotemporal dementia; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress; RNA-binding proteins
    DOI:  https://doi.org/10.1186/s12964-026-03082-w
  13. Front Neural Circuits. 2026 ;20 1870424
    Volume electron microscopy in axon regeneration research: insights into mitochondria, endoplasmic reticulum, and membrane contacts.
    Hiromi Tamada.
      Analysing organelle structures in tissue samples that preserve the in vivo environment, rather than in isolated cells, can provide valuable information on the mechanisms underlying nerve recovery and repair. However, determining organelle ultrastructure within tissue samples remains challenging with conventional microscopic techniques. To address this limitation, volume electron microscopy, particularly focused ion beam/scanning electron microscopy (FIB/SEM), has provided novel insights into organelle morphology, distribution, and membrane contacts, in three-dimensions and even within intact tissues. This review highlights the application of FIB/SEM for exploring the three-dimensional organization of mitochondria in motor neuron cell bodies and along the axon initial segments (AIS), where simultaneous investigation of intracellular and extracellular environments is difficult using other approaches. These analyses have revealed novel findings regarding mitochondrial distribution under healthy conditions and its dramatic alteration following injury, as well as microglial attachment around the AIS. Furthermore, FIB/SEM has enabled detailed characterization of the complex endoplasmic reticulum (ER) architecture within motor neuron cell bodies. Three-dimensional reconstructions have demonstrated a distinct uneven distribution of the ER in healthy neurons and revealed disruption of this organization following injury. In addition, ER-plasma membrane (ER-PM) contacts have been characterized as sheet-like structures, and quantitative analyses have shown significant increases in ER-PM contacts after injury. The novel findings obtained through FIB/SEM provide new perspectives on the cellular mechanisms underlying neuroregeneration and highlight the value of volume electron microscopy in advancing our understanding of nerve repair processes.
    Keywords:  axon initial segment; endoplasmic reticulum; focused ion beam/scanning electron microscopy; microglia; mitochondria; peripheral nerve injury; volume electron microscopy
    DOI:  https://doi.org/10.3389/fncir.2026.1870424
  14. Eur J Neurol. 2026 Jul;33(7): e70704
    Plasma Proteomic Changes in GRN and C9orf72 Frontotemporal Dementia.
    Joel Simrén, Andrea L Benedet, Guglielmo Di Molfetta, Ilaria Pola, Kübra Tan, Valentina Cantoni, Ilenia Libri, Jasmine Rivolta, Roberta Ghidoni, Henrik Zetterberg, Barbara Borroni, Nicholas J Ashton.
       BACKGROUND: Biomarkers reflecting the complex pathophysiology of genetic frontotemporal dementia (FTD) will be increasingly important with the advent of therapeutic trials aiming to slow or prevent the disease. In this study, we aimed to identify blood biomarker candidates using a multiplex panel of CNS-related proteins.
    METHODS: We cross-sectionally evaluated 67 carriers (21 presymptomatic and 46 symptomatic) of pathogenic FTD-causing mutations in the GRN (n = 30 symptomatic) and C9orf72 (n = 16 symptomatic) genes and 42 matched non-carriers. Clinical severity was estimated using the CDR Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR plus NACC FTLD). A total of 124 CNS-related proteins were measured in plasma using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) CNS panel. Group-level changes were then investigated using linear and non-linear regression models.
    RESULTS: In GRN- and C9orf72-FTD, neurofilament light (NfL) was the most clearly altered protein compared with non-carriers (GRN: β [95% CI] = 4.0 standard deviations [3.6-4.4], C9orf72: β = 2.8 [2.2-3.4]), followed by neurofilament heavy (NfH; GRN: β = 0.83 [0.39-1.3], C9orf72: β = 1.4 [0.8-2.0]). Proteins exclusively altered in GRN-FTD included glial fibrillary acidic protein (GFAp; β = 0.50 [0.20-0.81]) and vascular cell adhesion protein 1 (VCAM1; Standardized β = -0.90 [-1.4 to -0.38]), changing with increasing disease severity. Neuronal pentraxin receptor (NPTXR; β = -0.94 [-1.5 to -0.4]) was selectively reduced in C9orf72-FTD. Nominally changed proteins in C9orf72-FTD included several inflammatory mediators.
    CONCLUSIONS: Using this multiplex panel, established markers recapitulated previously established trends, while less-studied biomarker candidates were also identified. If validated in independent cohorts, these candidates could broaden the repertoire of blood biomarkers reflecting genetic FTD pathophysiology.
    Keywords:  biomarkers; frontotemporal dementia; proteomics
    DOI:  https://doi.org/10.1111/ene.70704
  15. Elife. 2026 Jul 14. pii: e112225. [Epub ahead of print]15
    Understanding the cellular architecture of Huntington's disease.
    Dorian Pustina.
      A new diffusion MRI approach offers a glimpse of the anomalies of cellular architecture underlying basal ganglia degeneration in Huntington's disease.
    Keywords:  Huntington's; Imaging; Neurite Density; human; neurodegeneration; neuroscience
    DOI:  https://doi.org/10.7554/eLife.112225
  16. Trends Neurosci. 2026 Jul 11. pii: S0166-2236(26)00120-7. [Epub ahead of print]
    Targeting DNA mismatch repair in Huntington's disease.
    Emma L Bunting, Amol Panhale, Peter McColgan, Minoru Koi, Patrik Brundin, John M Carethers.
      Somatic expansion of the HTT CAG repeat is a key feature of Huntington's disease (HD) pathogenesis. Mismatch repair (MMR) enzymes drive this process through erroneous DNA repair, with variants in MMR genes modifying the onset and progression of disease features. Cell-type-specific CAG repeat sizing recently confirmed that elevated somatic expansion underlies the selective vulnerability of HD medium spiny neurons, with expansion beyond certain CAG thresholds associated with distinct stages of cellular pathogenesis. In this review, we synthesise insights from post-mortem brain tissue, cell systems, and mouse models, detailing key CAG repeat-length-dependent changes. In addition, we critically evaluate the MMR proteins MSH3, MLH3, and PMS1 as therapeutic targets for slowing somatic expansion and outline key safety considerations for emerging MMR-modulating approaches.
    Keywords:  genetic modifiers; microsatellite instability; polyposis; somatic expansion; therapeutic targets; transcriptionopathy
    DOI:  https://doi.org/10.1016/j.tins.2026.06.004
  17. Commun Biol. 2026 Jul 15.
    Label-free segmentation of mitochondria for simultaneous morphological and metabolic studies.
    Kideog Bae, Muzaffer Özbey, Alexander Ho, Edita Aksamitiene, Kevin K D Tan, Janet E Sorrells, Rishyashring R Iyer, Mark A Anastasio, Stephen A Boppart.
      The dynamics in the mitochondrial structure and function are closely related to cellular health. Traditional fluorescence imaging techniques for observing mitochondria are limited by phototoxicity, photobleaching and staining artifacts. In this study, we propose RedoxSegNet, an AI-enhanced imaging platform that enables label-free segmentation of mitochondria for concurrent morphological and functional analysis without the aid of labeling dyes. Our approach uses high-resolution two-photon excitation fluorescence microscopy, in conjunction with a custom-built conditional diffusion model, to reconstruct mitochondrial features from NAD(P)H autofluorescence images. Subsequent segmentation through post-processing algorithms demonstrates a task-specific performance error of less than 6% on average compared to the mitochondria-stained images. Our trained model effectively extracts mitochondrial features from label-free images, thereby facilitating mapping of mitochondria-specific optical redox ratios. We find that our analysis elucidates metabolic heterogeneity both within and between the organelles. Further validation under mitochondrial stress conditions induced by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) confirms that RedoxSegNet can capture dynamic mitochondrial fragmentation and heterogeneous metabolic response. Overall, these findings establish our technique as a non-invasive, reliable tool for investigating mitochondrial morpho-functional dynamics in native cellular environments.
    DOI:  https://doi.org/10.1038/s42003-026-10687-x
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