Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington's disease
Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington's disease
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DOI：
10.1523/jneurosci.3183-05.2005
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发表时间：
2005-10-19
影响因子：
5.3
通讯作者：
Lucas, JJ
中科院分区：
文献类型：
--
作者：
Díaz-Hernández, M;Torres-Peraza, J;Lucas, JJ
导致亨廷顿病的主要机制仍然未知。假定的早期致病事件包括以下：蛋白质折叠受损、蛋白质降解改变、线粒体功能障碍和转录失调。尽管相关疗法可以延缓小鼠模型中的疾病进展，但它们靶向于muplatin-亨廷顿蛋白表达的下游和可能的间接作用。因此，如果它们被证明对人类有益，它们可能只会减轻疾病的某些方面。我们以前在泰特/HD 94条件模型中的研究和最近报道的RNA干扰在另一种小鼠模型中对突变亨廷顿蛋白的功效支持沉默突变亨廷顿蛋白表达作为一种有效的治疗方法，其具有从根本上靶向毒性的优势。在这里，我们解决基因沉默是否仍然可以在疾病的晚期阶段与可检测的纹状体神经元损失是有益的。应用体视学分析来确定泰特/HD 94小鼠显示纹状体神经元数量减少的年龄。然后，在允许继续表达突变亨廷顿蛋白的小鼠和不再表达突变亨廷顿蛋白的小鼠中分析神经病理学和运动表型的进展。在基因关闭的小鼠中，神经元损失没有恢复，但在基因开启的小鼠中发生的额外损失被阻止。含亨廷顿蛋白的包涵体的总数急剧恢复，但仍有一小部分对淀粉样蛋白染料硫磺素-S呈阳性的包涵体。有趣的是，尽管纹状体神经元减少了20%，并且存在淀粉样不可逆内含物，但基因关闭小鼠完全从其运动缺陷中恢复，从而排除了淀粉样亨廷顿蛋白内含物作为主要毒性物质，并表明基因沉默疗法可能在疾病的晚期阶段起作用。
The primary mechanism responsible for Huntington's disease remains unknown. Postulated early pathogenic events include the following: impaired protein folding, altered protein degradation, mitochondrial dysfunction, and transcriptional dysregulation. Although related therapies can delay disease progression in mouse models, they target downstream and probably indirect effects of mutant-huntingtin expression. Accordingly, in case they prove beneficial in humans, they might only palliate some aspects of disease. Our previous studies in the Tet/HD94 conditional model and the recently reported efficacy of RNA interference against mutant huntingtin in another mouse model support silencing mutant-huntingtin expression as a valid therapeutic approach that has the advantage of targeting toxicity at its root. Here, we address whether gene silencing can still be beneficial in the late stages of disease with detectable striatal neuron loss. Stereological analysis was applied to determine an age at which Tet/HD94 mice show a decrease in the number of striatal neurons. Then, progression of neuropathology and motor phenotype were analyzed in mice that were allowed to continue expressing mutant huntingtin and in mice that no longer expressed it. Neuronal loss did not revert in gene-off mice, but the additional loss that takes place in gene- on mice was prevented. The total number of huntingtin-containing inclusions dramatically reverted, but a small fraction of inclusions positive for the amyloid dye thioflavin-S remained. Interestingly, despite a 20% decrease in striatal neurons and the presence of amyloid-like irreversible inclusions, gene-off mice fully recover from their motor deficit, thus ruling out amyloid-like huntingtin inclusions as the main toxic species and suggesting that gene-silencing therapies might work in late stages of disease.