TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets
TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets
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DOI：
10.1172/jci124481
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发表时间：
2019-09-03
影响因子：
15.9
通讯作者：
Katsuno, Masahisa
中科院分区：
文献类型：
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作者：
Araki, Kunihiko;Araki, Amane;Katsuno, Masahisa
由TARDBP编码的TAR dna结合蛋白43 kDa （TDP-43）是一种rna结合蛋白，其核缺失是肌萎缩侧索硬化症（ALS）的组织病理学标志，ALS是一种影响上、下运动神经元的致命神经退行性疾病。除了运动症状外，ALS患者还经常出现非神经元性体征，如葡萄糖耐受不良，但其潜在的病理机制仍有争议，即是否为胰岛素分泌受损和/或胰岛素抵抗。在这里，我们发现ALS受试者早期胰岛素分泌减少，TDP-43的核定位在尸检的ALS胰腺的胰岛中丢失。在培养的β细胞系（MIN6）和β细胞特异性tardbp敲除小鼠中，TDP-43的缺失通过下调CaV1.2钙通道抑制胞吐，从而减少早期胰岛素分泌。在tardbp敲低的MIN6细胞中，过表达CaV1.2可恢复早期胰岛素分泌。我们的研究结果表明，TOP-43调节l型电压依赖性钙通道介导的细胞胞吐，因此在胰岛分泌胰岛素的早期阶段发挥重要作用。因此，TDP-43的核缺失不仅与运动神经元的选择性缺失有关，还与ALS早期胰岛素分泌受损导致的葡萄糖耐受不良有关。
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 beta cell line (MIN6) and beta cell-specific Tardbp-knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp-knocked-down MIN6 cells. Our findings suggest that TOP-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.