Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis.
Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis.
复制标题
在没有内蛋白水解作用的情况下，阿尔茨海默病相关的早老素 1 的淀粉样蛋白生成功能。
DOI：
10.1021/bi9914210
复制
发表时间：
1999
期刊：
影响因子：
2.9
通讯作者：
C. Haass
中科院分区：
文献类型：
--
作者：
H. Steiner;H. Romig;B. Pesold;U. Philipp;M. Baader;M. Citron;H. Loetscher;H. Jacobsen;C. Haass
阿尔茨海默病（AD）的特征在于主要由病理相关的42-氨基酸淀粉样β-肽（A β 42）组成的老年斑的不变积累。早老素（PS）蛋白在Abeta产生中起关键作用。PS1和PS2中的FAD相关突变增强了Abeta 42的产生，并且PS1是生理Abeta产生所需的，因为PS1的基因敲除和PS1的显性负突变消除了Abeta产生。PS蛋白进行内切蛋白水解加工，目前的证据表明，片段的形成可能需要的淀粉样蛋白的功能PS。我们现在已经确定了PS1内蛋白水解的序列要求。在先前确定的主要裂解位点（氨基酸298）的诱变氨基酸对PS1内蛋白水解没有影响。相反，在氨基酸292周围的额外切割位点处的突变或缺失阻断了内蛋白水解。不可裂解的PS1衍生物积累为全长蛋白，并取代内源性PS1蛋白。与之前描述的跨膜结构域6和7内的天冬氨酸突变相反，未切割的PS1变体并不充当Abeta产生的显性负性抑制剂。此外，当FAD相关突变（M146 L）与阻断内蛋白水解的突变相结合时，A β 42的产生仍然达到病理水平。因此，这些数据表明，早老素的内蛋白水解不是PS1的淀粉样蛋白生成功能的绝对先决条件。这些数据还表明，积累的PS1全蛋白是不相关的PS1突变的病理活动，如前所述。
Alzheimer's disease (AD) is characterized by the invariant accumulation of senile plaques predominantly composed of the pathologically relevant 42-amino acid amyloid beta-peptide (Abeta42). The presenilin (PS) proteins play a key role in Abeta generation. FAD-associated mutations in PS1 and PS2 enhance the production of Abeta42, and PS1 is required for physiological Abeta production, since a gene knockout of PS1 and dominant negative mutations of PS1 abolish Abeta generation. PS proteins undergo endoproteolytic processing, and current evidence indicates that fragment formation may be required for the amyloidogenic function of PS. We have now determined the sequence requirements for endoproteolysis of PS1. Mutagenizing amino acids at the previously determined major cleavage site (amino acid 298) had no effect on PS1 endoproteolysis. In contrast, mutations or deletions at the additional cleavage site around amino acid 292 blocked endoproteolysis. The uncleavable PS1 derivatives accumulated as full-length proteins and replaced the endogenous PS1 proteins. In contrast to the previously described aspartate mutations within transmembrane domains 6 and 7, the uncleaved PS1 variants do not act as dominant negative inhibitors of Abeta production. Moreover, when a FAD-associated mutation (M146L) was combined with a mutation blocking endoproteolysis, Abeta42 production still reached pathological levels. These data therefore demonstrate that endoproteolysis of presenilins is not an absolute prerequisite for the amyloidogenic function of PS1. These data also show that accumulation of the PS1 holoprotein is not associated with the pathological activity of PS1 mutations as suggested previously.