Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer's Disease.
Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer's Disease.
复制标题
DOI：
10.3233/jad-200598
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Johnson GVW
中科院分区：
文献类型：
--
作者：
Deaton CA;Johnson GVW
编码早老素1 （PS1）的PSEN1基因突变是家族性阿尔茨海默病（fAD）的最常见原因。自25年前首次发现PSEN1基因突变以来，人们对PS1的许多假设功能进行了研究。早期的研究主要集中在其作为γ-分泌酶复合物的催化组分的作用上，该复合物与β位点淀粉样蛋白前体蛋白切割酶1 （BACE1）协同，介导淀粉样蛋白-β前体（a -β pp）形成a -β。虽然突变体PS1最初被认为是通过其蛋白酶功能促进a β病理导致AD，但现在已经清楚PS1是一种参与调节膜动力学和蛋白质运输的多功能蛋白。因此，通过这些能力的丧失，突变体PS1有可能损害许多细胞功能，如钙通量、不同区室中蛋白质的组织和通过液泡代谢的蛋白质周转。钙信号受损、空泡功能障碍、线粒体功能障碍和内质网应激增加，以及其他相关的膜依赖性紊乱，被认为是AD发生和发展的关键因素。鉴于PS1在所有这些过程中起着关键的调节作用，本综述将描述PS1在不同细胞区室中的作用，并提供PS1失调（由于突变或其他原因）如何导致各种细胞过程的损伤，并导致“多重打击”，综合病理结果，这可能有助于AD的病因学。
Mutations in the PSEN1 gene, encoding presenilin 1 (PS1), are the most common cause of familial Alzheimer’s disease(fAD). Since the first mutations in the PSEN1 gene were discovered more than 25 years ago, many postulated functions of PS1 have been investigated. The majority of earlier studies focused on its role as the catalytic component of the γ-secretase complex, which in concert with β site amyloid precursor protein cleaving enzyme 1 (BACE1), mediates the formation of Aβ from amyloid-β protein precursor (AβPP). Though mutant PS1 was originally considered to cause AD by promoting Aβ pathology through its protease function, it is now becoming clear that PS1 is a multifunctional protein involved in regulating membrane dynamics and protein trafficking. Therefore, through loss of these abilities, mutant PS1 has the potential to impair numerous cellular functions such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism. Impaired calcium signaling, vacuolar dysfunction, mitochondrial dysfunction, and increased ER stress, among other related membrane-dependent disturbances, have been considered critical to the development and progression of AD. Given that PS1 plays a key regulatory role in all these processes, this review will describe the role of PS1 in different cellular compartments and provide an integrated view of how PS1 dysregulation (due to mutations or other causes) could result in impairment of various cellular processes and result in a “multi-hit”, integrated pathological outcome that could contribute to the etiology of AD.