Mutations in the COPI coatomer subunit α-COP induce release of Aβ-42 and amyloid precursor protein intracellular domain and increase tau oligomerization and release.
Mutations in the COPI coatomer subunit α-COP induce release of Aβ-42 and amyloid precursor protein intracellular domain and increase tau oligomerization and release.
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DOI：
10.1016/j.neurobiolaging.2021.01.003
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发表时间：
2021-05
影响因子：
4.2
通讯作者：
Custer SK
中科院分区：
文献类型：
--
作者：
Astroski JW;Akporyoe LK;Androphy EJ;Custer SK
阿尔茨海默病（AD）是痴呆症最常见的病因，折磨着超过500万美国人；它是美国第六大死因。随着人口的老龄化，患阿尔茨海默病的美国人数量预计会急剧增加。了解导致AD病理的细胞过程对于设计有意义的治疗干预措施至关重要。AD的特点是聚集蛋白的积累，这些蛋白可能是有毒的，可能代表细胞无法正常处理这些蛋白。了解散发性阿尔茨海默病的一个关键在于具有高度渗透病史的家族遗传学。在患有AD的家庭中发现了称为COPI的细胞运输复合物亚基突变，而没有其他已知的AD相关突变。COPI复合体参与细胞内的蛋白质加工和运输。有趣的是，最近的一些出版物发现COPI复合物的成分可以影响致病性AD蛋白的代谢。我们在这里报道，降低COPI亚基α-COP的水平会改变淀粉样蛋白前体蛋白（APP）的成熟和裂解，导致Aβ - 42的释放减少，APP细胞内c端结构域的积累减少。我们还发现α-COP的缺失减少了蛋白病Tau种子的摄取并减少了细胞内Tau的自结合。α-COP中ad相关突变的表达改变了APP加工，导致Aβ - 42释放增加，细胞内Tau聚集和Tau低聚物释放增加。综上所述，这些结果表明，COPI涂层的功能调节了APP和Tau的加工，而ad相关α-COP突变蛋白的表达赋予了功能的毒性增益，从而导致APP和Tau的潜在致病性变化。
Alzheimer’s disease (AD) is the most common cause of dementia, afflicting more than 5 million Americans; it is the 6th leading cause of death in the United States. As the population ages, the number of Americans with AD expected to increase dramatically. Understanding the cellular processes that lead to AD pathology is critical to designing meaningful therapeutic interventions. AD is characterized by the accumulation of aggregated proteins that may be toxic and may represent failure of the cell to normally process these proteins. One key to understanding sporadic AD lies in the genetics of families with highly penetrant histories of the disease. Mutations in subunits of a cellular trafficking complex known as COPI were found in families with AD and no other known AD-associated mutations. The COPI complex is involved in protein processing and trafficking within the cell. Intriguingly, several recent publications have found that components of the COPI complex can affect the metabolism of pathogenic AD proteins. We report here that reducing levels of the COPI subunit α-COP alters maturation and cleavage of amyloid precursor protein (APP), resulting in decreased release of Aβ−42 and decreased accumulation of the APP intracellular C-terminal domain. We also found that depletion of α-COP reduces uptake of proteopathic Tau seeds and reduces intracellular Tau self-association. Expression of AD-associated mutations in α-COP altered APP processing, resulting in increased release of Aβ−42 and increased intracellular Tau aggregation and release of Tau oligomers. Taken together, these results show that COPI coatomer function modulates the processing of both APP and Tau and that expression of AD-associated α-COP mutant proteins confers a toxic gain of function, which results in potentially pathogenic changes in both APP and Tau.
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