The presenilins and Alzheimer's disease
The presenilins and Alzheimer's disease
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DOI：
10.1093/hmg/6.10.1639
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发表时间：
1997-01-01
影响因子：
3.5
通讯作者：
Hardy, J
中科院分区：
文献类型：
--
作者：
Hutton, M;Hardy, J
早老素1和早老素2基因已被鉴定为参与大多数早发性常染色体显性阿尔茨海默病的致病位点。在这两个基因中已鉴定出导致疾病的一系列（主要）错义突变。早老素可能是八个跨膜结构域蛋白，两端位于细胞质区室中。它们具有广泛的组织分布，并且在内质网和早期高尔基体中被发现，突变的发病机制尚不清楚，尽管在患者和体外系统中，早老素突变的影响使人联想到淀粉样前体蛋白基因中致病性突变的影响，其导致淀粉样β 42的量增加（43）因此，早老素数据为阿尔茨海默病发病机制的淀粉样级联假说提供了独立的支持，对早老素的秀丽隐杆线虫同系物spe-4和sel-12的研究，提示早老素可能在膜结合蛋白的加工和运输中具有更普遍和直接的作用，并且在某种程度上，致病性突变可能破坏这种作用。
The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease, A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The presenilins are probably eight transmembrane domain proteins with both termini in the cytoplasmic compartment. They have a wide tissue distribution and are found in the endoplasmic reticulum and early Golgi, The mechanism of pathogenesis of the mutations is not clear although, both in patients and in in vitro systems, the effects of presenilin mutations are reminiscent of the effects of the pathogenic mutations in the amyloid precursor protein gene which lead to increases in the amount of amyloid-beta 42(43) being produced from the metabolism of the amyloid protein precursor, Thus, the presenilin data provide independent support for the amyloid cascade hypothesis of Alzheimer's pathogenesis, Work on the Caenorhabditis elegans homologues of the presenilins, spe-4 and sel-12, suggests that the presenilins may have a more general and direct role in the processing and trafficking of membrane-bound proteins and that, in part, the pathogenic mutations may disrupt this role.