Neurobiology of Disease最新文献

Background: Cognitive deficits are common in spinocerebellar ataxia type 3 (SCA3), but their neurobiological correlates remain largely unknown.

Objectives: To investigate cognitive performance in a large international cohort of SCA3 mutation carriers covering the entire disease course and to explore associations with posterior cerebellar volumes, basal ganglia and thalamus volumes, and plasma neurofilament light chain (NfL) concentration.

Methods: The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive impairment in this prospective, observational cohort study involving 13 ataxia referral centers. Standardized motor assessments, brain MR imaging, and peripheral blood biosampling were also performed.

Results: MoCA data were collected from 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls. After adjustments for educational level and age, there were significant differences in MoCA total score, as well as visuospatial/executive, attention, language, and abstraction subscores, between healthy controls and ataxic, but not pre-ataxic individuals. MoCA scores declined with ataxia severity, especially in patients with a lower educational level. Patients with a MoCA score < 26 had lower pallidal volumes and higher plasma NfL concentrations than those with a score ≥ 26. However, only the interaction term between ataxia severity and educational level was independently associated with cognitive performance in multivariable regression analyses containing demographic, clinical, volumetric, and biochemical parameters.

Conclusion: Cognitive deficits in SCA3 generally appear after clinical ataxia onset and progress in parallel with ataxia severity, especially in patients with a lower cognitive reserve. Other measured biochemical and imaging parameters did not have a significant additional contribution.

Although early telencephalic interneuron dysfunction in animal models and cortical interneuron deficits in Huntington's disease (HD) have been documented, their developmental origins and causal contributions to disease pathogenesis remain incompletely understood. Using the BACHD mouse model, we examined medial ganglionic eminence (MGE)-derived GABAergic lineage development across embryonic and early postnatal stages, integrated single-cell transcriptomic analyses of E12.5 MGE progenitors and assessed disease relevance through lineage-specific genetic rescue. At postnatal day (PND) 13, BACHD mice exhibited reduced numbers of cortical somatostatin-positive (SST⁺) and parvalbumin-positive (PV⁺) interneurons, as well as striatal PV⁺ interneurons, accompanied by a selective expansion of a Foxp2⁺ arkypallidal neuron subpopulation in the globus pallidus. By PND30, PV⁺ interneuron deficits were no longer detected, whereas cortical SST⁺ interneuron reductions persisted. Single-cell RNA sequencing revealed that mutant huntingtin disrupts early MGE neurogenic programs, with basal intermediate progenitors representing a primary site of cell vulnerability. These cells displayed coordinated repression of replication-dependent histone genes, reduced expression of the chromatin regulator Erh, mitochondrial and ribosomal deficits, and altered cell-cycle dynamics characterized by S-phase accumulation without increased mitotic output. Consistent with these findings, immunohistochemical analyses revealed reduced interneuron precursors within E12.5 subpallial migratory corridors and increased Nkx2-1⁺/Dlx1⁺ precursors in developing globus pallidus regions. Importantly, conditional excision of mutant Htt within Nkx2-1-derived MGE lineages rescued early interneuron deficits, HD-like motor impairments and striatal degeneration. Together, these findings identify disrupted MGE neurogenesis as a key developmental mechanism contributing to HD pathogenesis and highlight associated vulnerabilities as potential early-stage disease-modifying targets.

Volume-regulated anion channels (VRACs) are central to cell volume homeostasis. They mediate swelling-induced efflux of chloride and organic osmolytes to drive regulatory volume decrease. In the brain, VRACs have been proposed to play a key role in astrocytic volume regulation. Genetic defects in astrocytic VRAC modulating proteins (MLC1, GlialCAM, Aquaporin-4, GPRC5B) cause the leukodystrophy Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by chronic white matter edema and myelin vacuolization. Disrupted VRAC activity in MLC-patient-derived lymphoblasts and primary astrocytes from MLC mice further supports a pathogenic link between defective VRAC activity and MLC. Here, we studied the physiological and pathological consequences of astrocyte-specific removal of the essential VRAC subunit LRRC8A. In contrast to established MLC mouse models, astrocyte specific Lrrc8a knockout mice had normal brain water content, no myelin vacuolization, and preserved expression of MLC-related proteins. At a late age they developed a mildly ataxic gait and displayed increased severity of kainate-induced seizures. Two-photon imaging in acute brain slices revealed that astrocytes lacking LRRC8A show normal volume recovery and chloride dynamics upon high potassium-induced cell swelling. Together, these findings demonstrate that astrocyte LRRC8A is not essential for volume regulation in situ and that its loss alone is insufficient to cause the chronic white matter edema typical of MLC. The mild neurological deficits indicate a physiological role for astrocyte LRRC8A, but MLC pathology likely arises from broader dysregulation of the astrocytic protein complex coordinating ion and water homeostasis.

Fragile X syndrome (FXS) is the most common inherited intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Although the pathological mechanisms underlying this neurodevelopmental disorder are challenging, recent studies have increasingly highlighted the involvement of glial cells in the pathogenesis of both ASD and FXS. Microglia and astrocytes are critical for brain development and homeostasis; thus, understanding glial dysfunction in both the developing and adult brain in these disorders may reveal novel therapeutic targets beyond the neuro-centric perspective. In this study, we demonstrated that the loss of function of Fmrp leads to phenotypic changes in both microglia and astrocytes within the hippocampus of the recently validated Fmr1-^∆exon 8 rat model of FXS without a significant induction of pro-inflammatory cytokines. For the first time, we also provide evidence that these non-inflammatory changes in glia are associated with dysmorphic nuclei and a reduced expression of Lamin B1, a key component of the nuclear envelope and an important modulator of brain development and aging, in the hippocampus of young adult Fmr1-^∆exon 8 rats. Collectively, our findings strengthen existing evidence of the glial contribution to FXS and identify Lamin B1 loss and nuclear abnormalities as potential early markers of hippocampal pathology, providing a novel potential molecular target which should be furtherly considered.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2-3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.

The ventrolateral periaqueductal gray (vlPAG) functions as a critical hub in the descending pain modulatory system. The vlPAG receives and processes upstream pain information, which is involved in descending pain modulation through projecting downstream to rostroventral medulla (RVM) or locus coeruleus (LC). Although the modulatory roles of the upstream pathways and the vlPAG-RVM connection in neuropathic pain have been extensively studied, but the involvement of the vlPAG-LC neural pathway in regulating neuropathic pain and related comorbidity requires further investigation. In the present study, the excitability of the vlPAG-LC pathway was found to be increased in spared nerve injury (SNI) mice. Activating of the vlPAG-LC pathway using chemogenetic approach produced antinociceptive and anxiolytic effects in SNI mice. Intrathecal administration of α2-adrenergic receptor antagonist reversed analgesic effect of the vlPAG-LC pathway in SNI mice. However, the anxiolytic effect of this neural pathway was unaffected. A previously unrecognized vlPAG-LC-anterior cingulate cortex (ACC) tertiary pathway was identified in the current work. The excitability of ACC increased in SNI mice, whereas decreased following activation of the vlPAG-LC pathway. Activation of the ACC pyramidal neurons blocked the vlPAG-LC pathway-mediated anxiolytic effect but not analgesic effect in SNI mice. Furthermore, the anxiolytic effect of the vlPAG-LC pathway in SNI mice was altered after activation of the LC-ACC pathway or microinjection of norepinephrine into ACC. The present results underscored spinal dorsal horn and ACC as the potential downstream targets for analgesic and anxiolytic effects of the vlPAG-LC neural pathway in SNI mice, respectively.

Neuronal differentiation requires precise coordination of progenitor proliferation, lineage commitment, and chromatin regulation to establish functional brain architecture. Host Cell Factor-1 (HCF-1), an X-linked transcriptional co-regulator linked to human intellectual disability, is essential for early development, yet its lineage-specific roles during mammalian neurogenesis remain incompletely defined. Here, we investigate the function of the HCF-1-OGT axis during neuronal differentiation and forebrain development. Early embryonic loss of HCF-1 resulted in developmental arrest due to gastrulation defects, while conditional deletion in Nkx2.1-derived neuronal lineages caused pronounced cortical disorganization, reduced GABAergic interneuron survival, and severe defects in forebrain commissures, including the corpus callosum and anterior commissure. These abnormalities were not observed following glial-restricted deletion, indicating a neuron-specific requirement for HCF-1. Neuronal ablation alone did not phenocopy these defects; however, combined neuronal ablation and HCF-1 loss exacerbated cortical and commissural abnormalities, revealing increased neuronal vulnerability. Transcriptomic profiling following HCF-1 depletion identified widespread dysregulation of gene networks associated with neuronal differentiation, synaptic organization, chromatin regulation, and axon guidance. Consistently, HCF-1 directly occupied promoters of key neuronal genes, including Elavl3 and NeuroD1, and its loss reduced activating chromatin marks at these loci. In vitro, depletion of HCF-1 or inhibition of OGT impaired neuronal proliferation, differentiation, and neurite outgrowth. Glycoproteomic analysis further revealed disruption of OGT-dependent protein networks involved in neuronal structure and maturation. Together, these findings identify HCF-1 as a central regulator of neuronal differentiation and forebrain organization and provide mechanistic insight into how disruption of the HCF-1-OGT axis contributes to neurodevelopmental disorders.

Neurodegenerative diseases represent a major and growing clinical challenge due to their progressive nature, biological heterogeneity, and limited therapeutic options. Recent advances in artificial intelligence (AI) have introduced new analytical strategies for extracting clinically relevant information from complex biomedical data, offering complementary tools to established diagnostic and research approaches. This review provides a critical and method-comparative synthesis of AI applications in neurodegenerative diseases, with emphasis on studies published between 2022 and 2025. Rather than cataloging algorithms, the review evaluates how specific AI methodologies are selected, implemented, and validated across diverse data modalities, including molecular profiles, neuroimaging, biosensors, speech, gait, and electronic health records. Across Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, the reviewed evidence indicates that AI-based models can support early risk stratification, disease characterization, and monitoring when applied within clearly defined analytic and clinical contexts. Importantly, performance gains are shown to depend strongly on data quality, feature representation, validation design, and alignment between model architecture and biological signal, rather than on algorithmic complexity alone. Emerging paradigms, including multimodal integration and next-generation AI frameworks, are discussed in relation to their methodological contributions rather than clinical readiness. By systematically comparing analytical strategies and highlighting sources of variability across studies, this review underscores the importance of methodological transparency, uncertainty-aware evaluation, and biological interpretability. Collectively, the work positions AI as an enabling and adjunctive analytical framework that can enhance neurodegenerative disease research and clinical decision support when deployed with rigor and caution, providing a balanced perspective on current capabilities and future directions.

Myotonic dystrophy type 1 (DM1) arises from toxic CUG-expanded DMPK transcripts that sequester Muscleblind-like (MBNL) proteins, yet how this molecular lesion perturbs brain development in congenital DM1 (CDM) remains unknown. Here, we identify an unanticipated developmental role for MBNL2 in outer radial glial cells, a progenitor population critical for cortical expansion. We demonstrate that MBNL2 is expressed in these cells both in vivo and in forebrain organoids derived from patient-specific human induced pluripotent stem cells (hiPSCs), rendering them particularly sensitive to MBNL2 titration. Using genome editing to excise the CTG repeats in the DMPK gene, we provide evidence that the expanded trinucleotide tract directly contributes to defective neuronal migration and impaired differentiation of late-born cortical neurons in CDM organoids. These findings redefine MBNL2 as a potential regulator of human corticogenesis and uncover a developmental mechanism by which RNA toxicity drives this severe form of DM1. By uncovering a prenatal origin for CDM neuropathology linked to MBNL2 dysfunction, this work opens avenues for therapeutic strategies targeting early developmental windows.

Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by the FMR1 premutation allele, is associated with brain degeneration, yet the mechanisms behind this neurodegeneration still need to be elucidated. Apoε polymorphism has been widely implicated in brain aging in cognitively healthy individuals and brain deterioration in Alzheimer's disease. This study aimed to examine the interaction of Apoε genotypes, FXTAS clinical symptoms, FMR1 molecular measures, and age, towards brain pathophysiology and cognitive functions. This longitudinal study includes MRI data collected from 205 male premutation carriers with and without FXTAS clinical symptoms and compared to 86 healthy male controls aged 40-85 years. The investigation includes FXTAS-related brain volumes, IQ, self-control behaviors, FMR1 molecular measures, and Apoε genotypes. In carriers with FXTAS, the presence of the Apoε2 allele showed a possible association with more favorable neuroimaging markers, such as reduced white matter hyperintensities, and lower incidence of the middle cerebellar peduncle sign, patterns that were not observed in carriers without FXTAS. Specifically, the presence of Apoε2 allele exhibited a potential protective effect on brain degeneration, and cognitive functions among FXTAS patients; on the contrary, the Apoε4 allele was associated with a worsening of brain volume and brain degeneration in carriers with no FXTAS symptoms. The identification of Apoε genotypes in FMR1 premutation carriers before any clinical symptoms of FXTAS are observed may improve symptomatic management leading to better outcomes for these individuals.