Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43–mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies–related diseases.

中文翻译：

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TDP-43 介导少突胶质细胞髓鞘形成所需的 SREBF2 调节基因表达

胆固醇代谢在中枢神经系统 (CNS) 内自主运作，其中大部分胆固醇存在于髓磷脂中。我们证明 TDP-43（肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的病理特征蛋白）会影响少突胶质细胞中的胆固醇代谢。TDP-43 直接与 SREBF2（胆固醇代谢的主要转录调节因子）的 mRNA 以及编码负责胆固醇生物合成和摄取的蛋白质（包括 HMGCR、HMGCS1 和 LDLR）的多种 mRNA 结合。TDP-43 耗竭会导致 SREBF2 和 LDLR 表达以及体外和体内胆固醇水平降低。TDP-43 介导的胆固醇水平变化可以通过重新引入 SREBF2 或 LDLR 来恢复。此外，补充胆固醇可以挽救 TDP-43 缺失引起的脱髓鞘。此外，来自 FTD 患者的具有 TDP-43 病理学的少突胶质细胞显示 HMGCR 和 HMGCS1 减少，以及 LDLR 和 TDP-43 共聚集。总的来说，我们的结果表明 TDP-43 在少突胶质细胞胆固醇稳态中发挥作用，胆固醇代谢异常可能与 TDP-43 蛋白病相关疾病有关。