Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice
Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice
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DOI：
10.1093/hmg/10.14.1511
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发表时间：
2001-07-01
影响因子：
3.5
通讯作者：
Zoghbi, HY
中科院分区：
文献类型：
--
作者：
Cummings, CJ;Sun, YL;Zoghbi, HY
许多神经退行性疾病是由功能获得机制引起的，在这种机制中，致病蛋白被改变，对细胞有毒，并聚集。这些“蛋白质病”包括阿尔茨海默氏症和帕金森氏症、普里恩病症和多谷氨酰胺病。后一组的成员，也称为三联体重复疾病，是由编码谷氨酰胺的不稳定CAG重复序列在各自的蛋白质中扩张引起的。脊髓小脑型共济失调1型(SCA1)就是这样一种疾病，其特征是由于小脑浦肯野细胞和脑干神经元的变性而导致运动协调能力的丧失。在SCA1和其他几种聚谷氨酰胺疾病中，膨胀的蛋白质聚集成核包涵体(NIS)。由于这些NIS积累了分子伴侣、泛素和蛋白酶体亚单位-细胞蛋白质重新折叠和降解机制的所有组件-我们假设蛋白质错误折叠和蛋白质清除受损可能是聚谷氨酰胺疾病的发病机制。在聚谷氨酰胺疾病的无脊椎动物模型中，过度表达特定的伴侣蛋白减少了转基因细胞中的蛋白质聚集，并抑制了神经退化。为了确定增强伴侣活性是否可以减轻哺乳动物模型中的表型，我们将SCA1小鼠与过度表达分子伴侣(诱导型HSP70或iHSP70)的小鼠杂交。我们发现，高水平的HSP70确实提供了防止神经退化的保护。
Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson's disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits-all components of the cellular protein re-folding and degradation machinery-we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration.