Medical Genetics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
Neurobiol Dis. 2009 Nov;36(2):280-92. doi: 10.1016/j.nbd.2009.07.020. Epub 2009 Aug 4.
Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) belongs to a group of autosomal dominant neurodegenerative diseases, which are caused by the expansion of a polyglutamine repeat in the affected protein, in this case ataxin-3. Ataxin-3 is mainly localized in the cytoplasm; however, one hallmark of SCA3 is the formation of ataxin-3-containing protein aggregates in the nucleus of neurons. Currently, it is not known how mutant ataxin-3 translocates into the nucleus. We performed localization assays of recently proposed and novel potential signals, functionally confirmed the activity of a nuclear localization signal, identified two novel nuclear export signals (NES 77 and NES 141), and determined crucial amino acids. In addition, we demonstrate the relevance of the identified signals for the intracellular localization of the N- and C-terminus of ataxin-3. Our findings stress the importance of investigating the mechanisms, which influence the intracellular distribution of ataxin-3 during the pathogenesis of SCA3.
脊髓小脑共济失调 3 型（SCA3）或 Machado-Joseph 病（MJD）属于一组常染色体显性神经退行性疾病，由受影响蛋白中的多聚谷氨酰胺重复扩展引起，在这种情况下为 ataxin-3。Ataxin-3 主要定位于细胞质中；然而，SCA3 的一个标志是神经元核中形成含有 ataxin-3 的蛋白聚集体。目前，尚不清楚突变的 ataxin-3 如何易位到细胞核中。我们进行了最近提出的和新的潜在信号的定位分析，功能上证实了核定位信号的活性，鉴定了两个新的核输出信号（NES77 和 NES141）和确定了关键氨基酸。此外，我们证明了所鉴定的信号对于 ataxin-3 的 N 端和 C 端在细胞内定位的相关性。我们的研究结果强调了研究影响 SCA3 发病机制期间 ataxin-3 细胞内分布的机制的重要性。
