新潟大学脳研究所分子神経疾患資源解析学分野・助教小池 佑佳Yuka KoikeDepartment of Molecular Neuroscience, Brain Research Institute, Niigata UniversityAbstractNuclear depletion and cytoplasmic aggregation of TDP-43 in the motor neurons are pathological hallmarks in amyotrophic lateral sclerosis (ALS) triggered by the aberrant levels of TDP-43. Since the expression levels of TDP-43 are strictly auto-regulated, it remains unclear why this autoregulatory function is disrupted. The risk factor for sporadic ALS is aging, which is associated with DNA methylation. Thus, we hypothesized that identifying the unique DNA methylation in the brains of ALS patients would shed light on the mechanism of the disease. We have revealed that 1) in the motor cortex, the autoregulatory region of TDP-43 is demethylated with aging, and the methylation percentages are inversely correlated with TDP-43 levels, and 2) DNA methylation age acceleration of TDP-43 autoregulatory region in the ALS is associated with the early onset. However, the specific methylation modifications characterizing ALS brains have not been found. One of the critical reasons is that DNA methylation status has been evaluated using whole tissues, containing a few affected cells and many unaffected cells in previous studies. In this project, we are focusing on TDP-43-depleted neuronal nuclei and evaluating the effects of DNA methylation on perturbations in RNA metabolism by a novel single-nuclei RNA/methylation sequencing technique (snmCAT-seq). This aims to clarify the roles of DNA methylation in ALS pathogenesis, especially in the early stages.はじめに筋萎縮性側索硬化症 (ALS) の病態機序として，核蛋白 TDP-43 量と分布の異常が想定される．しかし，TDP-43 量は，厳密に自己調節されるため，なぜ ALS で，その自己調節能が破綻するのか，不明であった．一方，孤発性 ALS の最大のリスクは加齢である．加齢には，DNA のメチル化修飾― 102 ―孤発性 ALS 罹患細胞の，単一核メチローム，トランスクリプトーム解析による病態解明The analyses of pathological cells in sporadic ALS by methylome and transcriptome at the single nuclei levels
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