Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hum Mol Genet. 2012 Jan 1;21(1):76-84. doi: 10.1093/hmg/ddr439. Epub 2011 Sep 23.
Spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant ataxia. The disease is caused by an expansion of a CAG-trinucelotide repeat region within the coding sequence of the ATXN3 gene, and this results in an expanded polyglutamine (polyQ) tract within the Ataxin-3 protein. The polyQ expansion leads to neuronal dysfunction and cell death. Here, we tested the ability of a number of proteins that interact with Ataxin-3 to modulate SCA3 pathogenicity using Drosophila. Of 10 candidates, we found four novel enhancers and one suppressor. The suppressor, PICK1 (Protein interacting with C kinase 1), is a transport protein that regulates the trafficking of ion channel subunits involved in calcium homeostasis to and from the plasma membrane. In line with calcium homeostasis being a potential pathway mis-regulated in SCA3, we also found that down-regulation of Nach, an acid sensing ion channel, mitigates SCA3 pathogenesis in flies. Modulation of PICK1 could be targeted in other neurodegenerative diseases, as the toxicity of SCA1 and tau was also suppressed when PICK1 was down-regulated. These findings indicate that interaction proteins may define a rich source of modifier pathways to target in disease situations.
脊髓小脑共济失调 3 型（SCA3）是最常见的常染色体显性共济失调。这种疾病是由 ATXN3 基因编码序列中 CAG-三核苷酸重复区域的扩展引起的，导致 Ataxin-3 蛋白内的扩展多聚谷氨酰胺（polyQ）片段。polyQ 扩展导致神经元功能障碍和细胞死亡。在这里，我们使用果蝇测试了许多与 Ataxin-3 相互作用的蛋白质调节 SCA3 致病性的能力。在 10 个候选蛋白中，我们发现了 4 个新的增强子和 1 个抑制子。抑制子 PICK1（与 C 激酶 1 相互作用的蛋白）是一种转运蛋白，可调节参与钙稳态的离子通道亚基向和远离质膜的运输。与钙稳态失调可能是 SCA3 中的潜在途径相一致，我们还发现，酸感应离子通道 Nach 的下调减轻了果蝇中的 SCA3 发病机制。下调 PICK1 可以针对其他神经退行性疾病进行靶向治疗，因为当下调 PICK1 时，SCA1 和 tau 的毒性也被抑制。这些发现表明，相互作用的蛋白质可能是疾病情况下靶向修饰途径的丰富来源。
