Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
Medical Scientist Training Program, University of Minnesota, Minneapolis, MN, 55455, USA.
Adv Exp Med Biol. 2018;1049:135-145. doi: 10.1007/978-3-319-71779-1_6.
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, inherited disease that leads to degeneration of Purkinje cells of the cerebellum and culminates in death 10-30 years after disease onset. SCA1 is caused by a CAG repeat mutation in the ATXN1 gene, encoding the ATXN1 protein with an abnormally expanded polyglutamine tract. As neurodegeneration progresses, other brain regions become involved and contribute to cognitive deficits as well as problems with speech, swallowing, and control of breathing. The fundamental basis of pathology is an aberration in the normal function of Purkinje cells affecting regulation of gene transcription and RNA splicing. Glutamine-expanded ATXN1 is highly stable and more resistant to degradation. Moreover, phosphorylation at S776 in ATXN1 is a post-translational modification known to influence protein levels. SCA1 remains an untreatable disease managed only by palliative care. Preclinical studies are founded on the principle that mutant protein load is toxic and attenuating ATXN1 protein levels can alleviate disease. Two approaches being pursued are targeting gene expression or protein levels. Viral delivery of miRNAs harnesses the RNAi pathway to destroy ATXN1 mRNA. This approach shows promise in mouse models of disease. At the protein level, kinase inhibitors that block ATXN1-S776 phosphorylation may lead to therapeutic clearance of unphosphorylated ATXN1.
脊髓小脑共济失调 1 型（SCA1）是一种成年起病的遗传性疾病，导致小脑浦肯野细胞退化，并在发病后 10-30 年内导致死亡。SCA1 是由 ATXN1 基因中的 CAG 重复突变引起的，该基因编码具有异常扩展的多谷氨酰胺链的 ATXN1 蛋白。随着神经退行性变的进展，其他大脑区域也会受到影响，导致认知缺陷以及言语、吞咽和呼吸控制问题。病理学的根本基础是浦肯野细胞正常功能的异常，影响基因转录和 RNA 剪接的调节。谷氨酸扩展的 ATXN1 高度稳定，更能抵抗降解。此外，ATXN1 中 S776 的磷酸化是一种已知影响蛋白质水平的翻译后修饰。SCA1 仍然是一种无法治愈的疾病，只能通过姑息治疗来管理。临床前研究基于这样一个原则，即突变蛋白负荷是有毒的，降低 ATXN1 蛋白水平可以缓解疾病。目前正在探索两种方法，一种是针对基因表达，另一种是针对蛋白水平。病毒递送的 miRNAs 利用 RNAi 途径来破坏 ATXN1 mRNA。这种方法在疾病的小鼠模型中显示出了前景。在蛋白水平上，阻断 ATXN1-S776 磷酸化的激酶抑制剂可能会导致未磷酸化 ATXN1 的治疗性清除。
