Characterization of detergent-insoluble complexes containing the familial Alzheimer's disease-associated presenilins
Characterization of detergent-insoluble complexes containing the familial Alzheimer's disease-associated presenilins
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DOI：
10.1046/j.1471-4159.1999.721534.x
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发表时间：
1999-04-01
影响因子：
4.7
通讯作者：
Hooper, NM
中科院分区：
文献类型：
--
作者：
Parkin, ET;Hussain, I;Hooper, NM
许多早发性家族性阿尔茨海默病的病例与编码早老素-1和早老素-2的两个基因内的突变有关。早老素是48-56-kDa蛋白质，其可以被蛋白水解切割以产生N-末端片段（类似于25-35 kDa）和C-末端片段（类似于17-20 kDa）。早老素-1的N-和C-末端片段，但不是全长早老素-1，在人类和小鼠大脑皮层和神经元和胶质瘤细胞系中很容易检测到，相比之下，早老素-2几乎只在大脑皮层中检测到的全长分子的分子量为56 kDa。早老素与洗涤剂不溶性，低密度膜微区，这些结构从大脑皮层中溶解在Triton X-100和随后的蔗糖密度梯度离心分离后的协会，也进行了检查。一小部分（10%）的N-和C-末端片段的早老素-1与洗涤剂不溶性，低密度膜微区，而一个相当大的比例全长早老素-2存在于相同的膜微区。此外，在富含β-肌动蛋白高密度、去污剂不溶性细胞骨架沉淀中存在显著比例的全长早老素-2。洗涤剂不溶性低密度膜微区中的早老素的存在表明这些专门的膜区域在脂双层内阿尔茨海默病相关蛋白的横向分离和/或这些蛋白的不同功能中可能起作用。
Many cases of early-onset familial Alzheimer's disease have been linked to mutations within two genes encoding the proteins presenilin-1 and presenilin-2. The presenilins are 48-56-kDa proteins that can be proteolytically cleaved to generate an N-terminal fragment (similar to 25-35 kDa) and a C-terminal fragment (similar to 17-20 kDa). The N- and C-terminal fragments of presenilin-1, but not full-length presenilin-1, were readily detected in both human and mouse cerebral cortex and in neuronal and glioma cell lines, in contrast, presenilin-2 was detected almost exclusively in cerebral cortex as the full-length molecule with a molecular mass of 56 kDa. The association of the presenilins with detergent-insoluble, low-density membrane microdomains, following the isolation of these structures from cerebral cortex by solubilization in Triton X-100 and subsequent sucrose density gradient centrifugation, was also examined. A minor fraction (10%) of both the N- and C-terminal fragments of presenilin-1 was associated with the detergent-insoluble, low-density membrane microdomains, whereas a considerably larger proportion of full-length presenilin-2 was present in the same membrane microdomains. in addition, a significant proportion of full-length presenilin-2 was present in a high-density, detergent-insoluble cytoskeletal pellet enriched in beta-actin. The presence of the presenilins in detergent-insoluble low-density membrane microdomains indicates a possible role for these specialized regions of the membrane in the lateral separation of Alzheimer's disease-associated proteins within the lipid bilayer and/or in the distinct functions of these proteins.