Chemical chaperones ameliorate neurodegenerative disorders in Derlin-1-deficient mice via improvement of cholesterol biosynthesis.
Chemical chaperones ameliorate neurodegenerative disorders in Derlin-1-deficient mice via improvement of cholesterol biosynthesis.
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DOI：
10.1038/s41598-022-26370-0
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发表时间：
2022-12-17
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
目前还没有针对神经退行性疾病潜在分子机制的治疗方法。虽然最近的分子伴侣疗法，减轻内质网（ER）应激显示在治疗神经退行性疾病的承诺，详细的机制仍然不清楚。我们以前报道过，中枢神经系统特异性缺失Derlin-1的小鼠，它编码ER质量控制的重要组成部分，是有用的神经退行性疾病，如脊髓小脑变性的模型。胆固醇的生物合成对大脑发育至关重要，它的破坏会抑制神经突的生长，导致脑萎缩。在这项研究中，我们报告了一种新的机制，化学伴侣改善脑萎缩和运动功能障碍。ER应激在Derlin-1缺陷小鼠的小脑中诱导，而施用化学伴侣并不能缓解ER应激。然而，化学伴侣治疗通过SREBP-2激活改善胆固醇生物合成障碍，同时缓解脑萎缩和运动功能障碍。总之，这些发现表明，ER应激可能不是分子伴侣疗法的作用靶点，并且化学分子伴侣介导的脑胆固醇生物合成的改善是神经退行性疾病的一种有前途的新型治疗策略。
There are no available therapies targeting the underlying molecular mechanisms of neurodegenerative diseases. Although chaperone therapies that alleviate endoplasmic reticulum (ER) stress recently showed promise in the treatment of neurodegenerative diseases, the detailed mechanisms remain unclear. We previously reported that mice with central nervous system-specific deletion of Derlin-1, which encodes an essential component for ER quality control, are useful as models of neurodegenerative diseases such as spinocerebellar degeneration. Cholesterol biosynthesis is essential for brain development, and its disruption inhibits neurite outgrowth, causing brain atrophy. In this study, we report a novel mechanism by which chemical chaperones ameliorate brain atrophy and motor dysfunction. ER stress was induced in the cerebella of Derlin-1 deficiency mice, whereas the administration of a chemical chaperone did not alleviate ER stress. However, chemical chaperone treatment ameliorated cholesterol biosynthesis impairment through SREBP-2 activation and simultaneously relieved brain atrophy and motor dysfunction. Altogether, these findings demonstrate that ER stress may not be the target of action of chaperone therapies and that chemical chaperone-mediated improvement of brain cholesterol biosynthesis is a promising novel therapeutic strategy for neurodegenerative diseases.
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对医疗统计信息的自由使用的易于使用的软件“ EZR”的调查。
影响因子：
4.8
作者：
Kanda Y
通讯作者：
Kanda Y
影响因子：
10.5
作者：
Nishitoh, H;Matsuzawa, A;Ichijo, H
通讯作者：
Ichijo, H
影响因子：
3.3
作者：
Bernardi, Kaleena M.;Williams, Jeffrey M.;Tsai, Billy
通讯作者：
Tsai, Billy
DOI：
10.1056/nejmoa1916945
发表时间：
2020-09-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
3
作者：
Iannitti T;Palmieri B
通讯作者：
Palmieri B