The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins.
The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins.
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作者：
Folger A;Wang Y
蛋白质错误折叠和聚集与许多神经退行性疾病有关。这些疾病之一是亨廷顿氏病，它是由亨廷顿基因内增加的谷氨酰胺编码三核苷酸重复序列引起的。与其他错误折叠的蛋白质一样，具有多聚谷氨酰胺扩增的突变亨廷顿蛋白易于聚集。错误折叠的蛋白质以可溶性单体、小聚集体或大的不溶性包涵体的形式存在。错误折叠的蛋白质聚集体被认为是细胞毒性的，通过强调蛋白质降解机制，破坏膜结构，或螯合其他蛋白质。我们最近发现错误折叠蛋白的表达降低了细胞内游离泛素的水平，这损害了蛋白质降解机制。因此，错误折叠蛋白质的有效降解对于保持细胞健康至关重要。细胞采用两种主要机制来降解错误折叠的蛋白质。第一个是泛素-蛋白酶体系统（UPS），其在分离酶Cdc 48/p97的协助下泛素化并降解错误折叠的蛋白质。UPS途径主要负责清除作为单体或较小聚集体存在的错误折叠蛋白质。第二种途径是巨自噬/自噬，其中蛋白质聚集体或包涵体在运输到液泡/溶酶体进行降解之前被募集到自噬体中。本文综述了目前对错误折叠蛋白的细胞毒性及其清除途径的认识，特别强调了突变亨廷顿蛋白。
Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.
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影响因子：
15.1
作者：
Ceballos-Diaz C;Rosario AM;Park HJ;Chakrabarty P;Sacino A;Cruz PE;Siemienski Z;Lara N;Moran C;Ravelo N;Golde TE;McFarland NR
通讯作者：
McFarland NR
影响因子：
10.5
作者：
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通讯作者：
Lindquist, Susan
影响因子：
16.6
作者：
Bard JAM;Goodall EA;Greene ER;Jonsson E;Dong KC;Martin A
通讯作者：
Martin A
影响因子：
64.5
作者：
Buchan, J. Ross;Kolaitis, Regina-Maria;Parker, Roy
通讯作者：
Parker, Roy
DOI：
10.1038/nrm.2016.74
发表时间：
2016-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Farré JC;Subramani S
通讯作者：
Subramani S