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C9orf72 林-氨酸二聚重复破坏蛋白质组并扰乱蛋白质分解活动
Yifan Zhang1, Sophia C K Nelson1, Ashley P Viera Ortiz2
1Department of Biology, Haverford College, Haverford, Pennsylvania, USA.
Journal of neuropathology and experimental neurology
|October 4, 2023
概括
在C9orf72-扩展ALS (C9ALS) 中发现的氨酸-氨酸 (polyPR) 聚合物会损害细胞蛋白质体. 这项研究证实了体内聚PR-蛋白酶的结合,揭示了C9ALS病变的关键机制.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- C9orf72 六核酸重复扩张是家族性肌缩侧面硬化症 (ALS) 的主要遗传原因.
- 异常翻译产生二聚重复 (DPR),包括神经毒性普罗林-阿尔金因 (polyPR).
- 之前的体外研究表明,polyPR会损害蛋白酶体的功能.
研究的目的:
- 在C9ALS患者组织和体内模型中确认和功能性描述PolyPR诱导的蛋白酶体损伤.
- 为了确定在体内polyPR-proteasome相互作用的临床相关性.
主要方法:
- 人类和Drosophila melanogaster脑组织中的共聚焦显微镜和免疫光.
- 在D. melanogaster.中进行共免疫沉降测定.
- 在体内分析蛋白质无化,溶酶体功能和用蛋白质体增强剂进行救援.
主要成果:
- 在人类和的大脑中,PolyPR被发现与蛋白质体隔离在类似包容体中.
- 通过共免疫沉证实了polyPR与蛋白质酶的直接结合.
- 在体内,蛋白质酶体损伤被ubiquitinated蛋白质积累和 lysosomal 功能障碍所证明,这些都是可逆的.
结论:
- 这项研究提供了第一份关于聚PR-蛋白酶相互作用的临床报告.
- 在体内证据表明,聚PR诱导的蛋白质分解功能障碍是C9orf72-扩展ALS (C9ALS) 的致病机制.
- 向蛋白酶体增强可能为C9ALS.提供治疗策略.
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