Department of Neurology.
Department of Endocrinology and Diabetes, and.
J Clin Invest. 2019 Jul 29;129(9):3578-3593. doi: 10.1172/JCI124481.
TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.
TAR DNA 结合蛋白 43kDa（TDP-43）由 TARDBP 编码，是一种 RNA 结合蛋白，其核内耗竭是肌萎缩侧索硬化症（ALS）的组织病理学特征，这是一种致命的神经退行性疾病，影响上下运动神经元。除运动症状外，ALS 患者常出现非神经元征象，包括葡萄糖耐量异常，但潜在的发病机制仍存在争议，即是否存在胰岛素分泌受损和/或胰岛素抵抗。在这里，我们发现 ALS 患者的早期胰岛素分泌减少，并且尸检 ALS 胰腺中的胰岛中 TDP-43 的核定位丢失。TDP-43 的缺失通过下调 CaV1.2 钙通道抑制胞吐作用，从而减少培养的β细胞系（MIN6）和β细胞特异性 Tardbp 敲除小鼠中的早期胰岛素分泌。CaV1.2 的过表达可恢复 Tardbp 敲低 MIN6 细胞中的早期胰岛素分泌。我们的研究结果表明，TDP-43 调节由 L 型电压依赖性钙通道介导的细胞胞吐作用，因此在胰岛的早期胰岛素分泌中发挥重要作用。因此，TDP-43 的核内丢失不仅与运动神经元的选择性丧失有关，而且与 ALS 早期胰岛素分泌受损导致的葡萄糖耐量异常有关。
