Hughes James N, Thomas Paul Q
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
Methods Mol Biol. 2013;1017:135-51. doi: 10.1007/978-1-62703-438-8_10.
Disease-causing polyalanine (PA) expansion mutations have been identified in nine genes, eight of which encode transcription factors (TFs) with important roles in development. In vitro and cell overexpression studies have shown that expanded PA tracts result in protein misfolding and the formation of aggregates. This feature of PA proteins is reminiscent of the related polyglutamine (PQ) disease proteins, which have been shown to cause disease via a gain-of-function (GOF) mechanism. However, in sharp contrast to PQ disorders, the disease phenotypes associated with PA mutations are more consistent with a LOF and/or mild GOF mechanism, suggesting that their molecular pathology is inherently different to PQ disorders. Elucidating the cellular impact of PA mutations in vivo has been difficult to address as, unlike the late-onset polyglutamine disorders, all PA disorders associated with TF gene mutations are congenital. However, in recent years, significant advances have been made through the analysis of engineered (knock-in) and spontaneous PA mouse models. Here we review these recent findings and propose an updated model of the molecular and cellular mechanism of PA disorders that incorporates both LOF and GOF features.
已在9个基因中鉴定出致病的聚丙氨酸（PA）扩展突变，其中8个基因编码在发育中起重要作用的转录因子（TFs）。体外和细胞过表达研究表明，扩展的PA序列会导致蛋白质错误折叠并形成聚集体。PA蛋白的这一特征让人联想到相关的聚谷氨酰胺（PQ）疾病蛋白，后者已被证明通过功能获得（GOF）机制致病。然而，与PQ疾病形成鲜明对比的是，与PA突变相关的疾病表型更符合功能丧失（LOF）和/或轻度GOF机制，这表明它们的分子病理学与PQ疾病本质上不同。由于与迟发性聚谷氨酰胺疾病不同，所有与TF基因突变相关的PA疾病都是先天性的，因此很难在体内阐明PA突变对细胞的影响。然而，近年来，通过对工程化（敲入）和自发的PA小鼠模型的分析取得了重大进展。在此，我们综述这些最新发现，并提出一个更新的PA疾病分子和细胞机制模型，该模型结合了LOF和GOF特征。
