Evers Melvin M, Toonen Lodewijk J A, van Roon-Mom Willeke M C
Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands.
Mol Neurobiol. 2014 Jun;49(3):1513-31. doi: 10.1007/s12035-013-8596-2. Epub 2013 Nov 29.
Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.
ataxin-3是一种广泛表达的去泛素化酶，在蛋白酶体蛋白降解途径和转录调控中具有重要功能。ataxin-3蛋白的C末端包含一个多聚谷氨酰胺（PolyQ）区域，当该区域发生突变扩展至超过52个谷氨酰胺时，会导致神经退行性疾病脊髓小脑共济失调3型（SCA3）。尽管进行了广泛研究，但突变型ataxin-3导致细胞毒性的分子机制仍不清楚，目前也没有预防性治疗方法。在过去十年中已经明确，细胞内标志性的ataxin-3聚集体可能不是SCA3中的主要毒性实体。相反，由半胱天冬酶和钙蛋白酶对ataxin-3进行蛋白水解切割产生的含可溶性PolyQ片段，现在被认为在发病机制中具有更大影响。此外，最近的证据表明RNA毒性成分可能参与SCA3和其他PolyQ扩展疾病，增加了致病复杂性。在此，我们综述了ataxin-3的功能以及已发现的突变型ataxin-3已知的蛋白质和RNA毒性机制的参与情况，以及未来治疗干预的机会。
