Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan; Department of Personalized Genomic Medicine for Health, Graduate School of Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Biochem Biophys Res Commun. 2024 Feb 5;695:149481. doi: 10.1016/j.bbrc.2024.149481. Epub 2024 Jan 5.
Spinocerebellar ataxia type 6 (SCA6) is a polyglutamine (polyQ) disease, which is caused by the elongation of CAG repeats encoding polyQ in the CACNA1A gene. The CACNA1A gene encodes two proteins, namely, α1A (a subunit of the plasma membrane calcium channel), which is translated in its entire length, and α1ACT, which is translated from the second cistron, and both proteins have a polyQ tract. The α1A-polyQ and α1ACT-polyQ proteins with an elongated polyQ stretch have been reported to form aggregates in cells and induce neuronal cell death, but the subcellular localization of these proteins and their cytotoxic properties remain unclear. In this study, we first analyzed SCA6 model mice and found that α1A-polyQ localized mainly to the Golgi apparatus, whereas a portion of α1ACT-polyQ localized to the nucleus. Analysis using Neuro2a cells also showed similar subcellular localizations of these proteins, and a proportion of both proteins localized to the endoplasmic reticulum (ER). Cytotoxic studies demonstrated that both proteins induce both the ER stress response and apoptosis, indicating that they are able to induce ER stress-induced apoptosis.
脊髓小脑性共济失调 6 型（SCA6）是一种多聚谷氨酰胺（polyQ）疾病，由 CACNA1A 基因中编码 polyQ 的 CAG 重复序列延长引起。CACNA1A 基因编码两种蛋白质，即全长翻译的 α1A（质膜钙通道的 a 亚基）和从第二个顺式元件翻译的 α1ACT，两者都具有 polyQ 片段。据报道，具有延长 polyQ 片段的 α1A-polyQ 和 α1ACT-polyQ 蛋白在细胞中形成聚集体并诱导神经元细胞死亡，但这些蛋白的亚细胞定位及其细胞毒性特性尚不清楚。在这项研究中，我们首先分析了 SCA6 模型小鼠，发现 α1A-polyQ 主要定位于高尔基体，而一部分 α1ACT-polyQ 定位于细胞核。使用 Neuro2a 细胞的分析也显示了这些蛋白的类似亚细胞定位，两者的一部分都定位于内质网（ER）。细胞毒性研究表明，这两种蛋白都诱导内质网应激反应和细胞凋亡，表明它们能够诱导内质网应激诱导的凋亡。
