Lee Davin, Lee Yun-Il, Lee Young-Sam, Lee Sung Bae
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea.
Well Aging Research Center, Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea.
Front Neurosci. 2020 Jun 4;14:489. doi: 10.3389/fnins.2020.00489. eCollection 2020.
Polyglutamine (polyQ) spinocerebellar ataxias (SCAs) are the most prevalent subset of SCAs and share the aberrant expansion of Q-encoding CAG repeats within the coding sequences of disease-responsible genes as their common genetic cause. These polyQ SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) are inherited neurodegenerative diseases characterized by the progressive atrophy of the cerebellum and connected regions of the nervous system, which leads to loss of fine muscle movement coordination. Upon the expansion of polyQ repeats, the mutated proteins typically accumulate disproportionately in the neuronal nucleus, where they sequester various target molecules, including transcription factors and other nuclear proteins. However, it is not yet clearly understood how CAG repeat expansion takes place or how expanded polyQ proteins accumulate in the nucleus. In this article, we review the current knowledge on the molecular and cellular bases of nuclear proteotoxicity of polyQ proteins in SCAs and present our perspectives on the remaining issues surrounding these diseases.
聚谷氨酰胺（polyQ）脊髓小脑共济失调（SCA）是最常见的SCA亚型，其共同的遗传病因是致病基因编码序列中编码谷氨酰胺的CAG重复序列异常扩增。这些polyQ SCA（SCA1、SCA2、SCA3、SCA6、SCA7和SCA17）是遗传性神经退行性疾病，其特征是小脑和神经系统相连区域进行性萎缩，导致精细肌肉运动协调能力丧失。随着polyQ重复序列的扩增，突变蛋白通常在神经元核中不成比例地积累，在那里它们隔离各种靶分子，包括转录因子和其他核蛋白。然而，目前尚不清楚CAG重复序列是如何扩增的，以及扩增的polyQ蛋白是如何在细胞核中积累的。在本文中，我们综述了目前关于SCA中polyQ蛋白核蛋白毒性的分子和细胞基础的知识，并就围绕这些疾病的其余问题提出了我们的观点。
