Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability
Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability
复制标题
DOI：
10.1523/jneurosci.0973-08.2008
复制
发表时间：
2008-08-27
影响因子：
5.3
通讯作者：
Hisanaga, Shin-ichi
中科院分区：
文献类型：
--
作者：
Kaminosono, Sayuko;Saito, Taro;Hisanaga, Shin-ichi
亨廷顿病（HD）是一种多聚谷氨酰胺[poly（Q）]疾病，在亨廷顿蛋白（htt）的N末端具有扩展的poly（Q）延伸。HD神经元的一个主要病理特征是包涵体，由聚（Q）扩增的突变htt（mhtt）组成的洗涤剂不溶性聚集体。mhtt的错误折叠被认为通过聚集体的形成而赋予毒性。虽然毒性分子种类仍有争议，但阐明聚集机制对理解mhtt的发病机制很重要。Westhow Cdk5/p35抑制细胞系和原代神经元中mhtt包涵体的形成。虽然我们在COS-7细胞中表达了缺少Cdk5磷酸化位点的htt的N-末端外显子1片段，但Cdk5的激酶活性是抑制所必需的。此外，Cdk5/p35抑制了另一种poly（Q）蛋白atrophin-1的包涵体形成，这提高了Cdk5/p35通常抑制poly（Q）蛋白包涵体形成的可能性。微管（MT）是Cdk5/p35抑制包涵体形成的下游组分; Cdk5/p35破坏MT，这是形成包涵体所必需的。此外，稳定的MTs紫杉醇诱导的夹杂物，甚至与Cdk5/p35的过度表达。包涵体的形成也通过操纵原代大鼠或小鼠皮层神经元培养物中的Cdk5/p35活性来调节。这些结果表明，MT组织的Cdk5依赖性调节参与了聚集体形成的发展和随后的多聚（Q）疾病的发病机制。这种Cdk5抑制htt聚集体是一种不同于先前报道的htt磷酸化和与Cdk5相互作用的新机制。
Huntington's disease (HD) is a polyglutamine [ poly(Q)] disease with an expanded poly(Q) stretch in the N terminus of the huntingtin protein (htt). A major pathological feature of HD neurons is inclusion bodies, detergent-insoluble aggregates composed of poly(Q)expanded mutant htt (mhtt). Misfolding of mhtt is thought to confer a toxic property via formation of aggregates. Although toxic molecular species are still debated, it is important to clarify the aggregation mechanism to understand the pathogenesis of mhtt. Weshow Cdk5/p35 suppresses the formation of mhtt inclusion bodies in cell lines and primary neurons. Although we expressed the N-terminal exon 1 fragment of htt lacking phosphorylation sites for Cdk5 in COS-7 cells, the kinase activity of Cdk5 was required for the suppression. Furthermore, Cdk5/p35 suppressed inclusion formation of atrophin-1, another poly(Q) protein, raising the possibility that Cdk5/p35 generally suppresses inclusion formation of poly(Q) proteins. Microtubules (MTs) were a downstream component of Cdk5/p35 in the suppression of inclusion formation; Cdk5/p35 disrupted MTs, which were required for the formation of inclusions. Moreover, stabilization of MTs by Taxol induced inclusions even with overexpression of Cdk5/p35. The formation of inclusions was also regulated by manipulating the Cdk5/p35 activity in primary rat or mouse cortical neuron cultures. These results indicate that Cdk5-dependent regulation of MT organization is involved in the development of aggregate formation and subsequent pathogenesis of poly(Q) diseases. This Cdk5 inhibition of htt aggregates is a novel mechanism different from htt phosphorylation and interaction with Cdk5 reported previously.