Protein Misfolding and Aggregation as a Therapeutic Target for Polyglutamine Diseases.
Protein Misfolding and Aggregation as a Therapeutic Target for Polyglutamine Diseases.
复制标题
DOI：
10.3390/brainsci7100128
复制
发表时间：
2017-10-11
期刊：
影响因子：
3.3
通讯作者：
Nagai Y
中科院分区：
文献类型：
--
作者：
Takeuchi T;Nagai Y
多聚谷氨酰胺（polyQ）疾病，如亨廷顿病和几种类型的脊髓小脑共济失调，是一组遗传性神经退行性疾病，其由致病蛋白中polyQ束的异常扩张引起。具有异常扩展的polyQ延伸的蛋白质经历构象转变为富含β-折叠的结构，其组装成具有富含β-折叠的淀粉样蛋白纤维结构的不溶性聚集体，并在神经元中作为包涵体积累，最终导致神经变性。由于扩增的polyQ蛋白的错误折叠和聚集是polyQ疾病的最常见致病级联中的最上游事件，因此它们被认为是开发polyQ疾病的疾病修饰疗法的最理想靶标之一。本文综述了polyQ疾病的分子致病机制，并介绍了针对polyQ蛋白错误折叠和聚集的治疗方法，这些方法不仅对多种polyQ疾病有效，而且广泛纠正了polyQ蛋白聚集过程中影响的多个下游细胞过程的功能异常。我们希望在不久的将来，开发出有效的治疗方法，为许多患有目前难治性polyQ疾病的患者带来希望。
The polyglutamine (polyQ) diseases, such as Huntington’s disease and several types of spinocerebellar ataxias, are a group of inherited neurodegenerative diseases that are caused by an abnormal expansion of the polyQ tract in disease-causative proteins. Proteins with an abnormally expanded polyQ stretch undergo a conformational transition to β-sheet rich structure, which assemble into insoluble aggregates with β-sheet rich amyloid fibrillar structures and accumulate as inclusion bodies in neurons, eventually leading to neurodegeneration. Since misfolding and aggregation of the expanded polyQ proteins are the most upstream event in the most common pathogenic cascade of the polyQ diseases, they are proposed to be one of the most ideal targets for development of disease-modifying therapies for polyQ diseases. In this review, we summarize the current understanding of the molecular pathogenic mechanisms of the polyQ diseases, and introduce therapeutic approaches targeting misfolding and aggregation of the expanded polyQ proteins, which are not only effective on a wide spectrum of polyQ diseases, but also broadly correct the functional abnormalities of multiple downstream cellular processes affected in the aggregation process of polyQ proteins. We hope that in the near future, effective therapies are developed, to bring hope to many patients suffering from currently intractable polyQ diseases.
登录
查看更多内容
影响因子：
6.1
作者：
Becher, MW;Kotzuk, JA;Ross, CA
通讯作者：
Ross, CA
影响因子：
30.8
作者：
ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
通讯作者：
HAYDEN, MR
影响因子：
4.5
作者：
Bañez-Coronel M;Porta S;Kagerbauer B;Mateu-Huertas E;Pantano L;Ferrer I;Guzmán M;Estivill X;Martí E
通讯作者：
Martí E
影响因子：
30.8
作者：
BANFI, S;SERVADIO, A;ZOGHBI, HY
通讯作者：
ZOGHBI, HY
影响因子：
30.8
作者：
DUYAO, M;AMBROSE, C;MACDONALD, M
通讯作者：
MACDONALD, M