Inhibition of Rho Kinases Enhances the Degradation of Mutant Huntingtin
Inhibition of Rho Kinases Enhances the Degradation of Mutant Huntingtin
复制标题
DOI：
10.1074/jbc.m809229200
复制
发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
--
作者：
Bauer, Peter O.;Wong, Hon Kit;Nukina, Nobuyuki
亨廷顿病（HD）是一种致命的遗传性神经退行性疾病，由亨廷顿蛋白（htt）中聚谷氨酰胺（polyQ）延伸扩张引起。虽然扩大的polyQ的病理意义已经明确确立，并且已经为开发HD的治疗工具付出了巨大的努力，但目前还没有有效的治疗方法。虽然已经发现了许多能够减少polyQ积累和聚集的分子，包括几种Rho激酶（ROCK）抑制剂，但确定潜在药物的作用机制仍然非常重要。据报道，包括Y-27632在内的ROCK抑制剂通过ROCK1和蛋白激酶c相关蛋白激酶2 （PRK-2）降低htt和雄激素受体（AR）的聚集。ROCK1的下游效应物，肌动蛋白结合因子profilin，被证明可以抑制突变体htt聚集，但不能通过直接相互作用抑制AR。我们发现ROCK抑制剂的抗聚集作用并不局限于突变体htt和AR， Y-27632也能够减少ataxin-3和atrophin-1的聚集。这些结果表明，除了报道的htt和AR机制外，可能还有其他常见的介质参与了不同polyQ蛋白聚集的减少。在这项研究中，我们发现Y-27632不仅通过增强其降解来减少突变体htt聚集，而且令人惊讶的是能够激活主要的细胞降解途径，蛋白酶体和巨噬。我们还发现这种独特的效应是由ROCK1和ROCK2介导的。
Huntington disease (HD) is a fatal hereditary neurodegenerative disease caused by an expansion of the polyglutamine (polyQ) stretch in huntingtin (htt). Whereas the pathological significance of the expanded polyQ has been clearly established and a tremendous effort to develop therapeutic tools for HD has been exerted, there is yet no effective cure. Whereas many molecules able to reduce the polyQ accumulation and aggregation have been identified, including several Rho kinase (ROCK) inhibitors, it remains very important to determine the mechanism of action of the potential drugs. ROCK inhibitors, including Y-27632 were reported to decrease aggregation of htt and androgen receptor (AR) through ROCK1 and protein kinase C-related protein kinase-2 (PRK-2). A downstream effector of ROCK1, actin-binding factor profilin, was shown to inhibit the mutant htt aggregation but not AR by direct interaction. We found that the anti-aggregation effect of ROCK inhibitors was not limited to the mutant htt and AR and that Y-27632 was also able to reduce the aggregation of ataxin-3 and atrophin-1 with expanded polyQ. These results suggested that in addition to the mechanism reported for htt and AR, there might also be other common mediators involved in the reduced aggregation of different polyQ proteins. In this study, we show that Y-27632 not only reduced the mutant htt aggregation by enhancing its degradation, but surprisingly was able to activate the main cellular degradation pathways, proteasome, and macroautophagy. We also show that this unique effect was mediated by ROCK1 and ROCK2.