Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia
Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia
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DOI：
10.1038/14783
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发表时间：
1999-11-01
影响因子：
25
通讯作者：
Sisodia, SS
中科院分区：
文献类型：
--
作者：
Kim, SH;Wang, R;Sisodia, SS
家族性英国痴呆（FBD）是一种常染色体显性遗传性神经退行性疾病，其遗传病变是BRI基因终止密码子的T-A颠换。突变基因编码BRI-L，ABri肽的前体，其在FBD脑中的淀粉样沉积物中积累。我们现在报告说，BRI-L和其野生型对应物，BRI，组成型处理的前蛋白转化酶，弗林蛋白酶，导致羧基末端肽的分泌，包括全部或部分的ABri。从突变体BRI前体产生升高水平的肽。电子显微镜研究显示，合成的ABri肽组装成不规则的短纤维。总的来说，我们的研究结果支持这样的观点，即增强弗林蛋白酶介导的突变BRI加工产生引发FBD发病机制的原纤维肽。
The genetic lesion underlying familial British dementia (FBD), an autosomal dominant neurodegenerative disorder, is a T-A transversion at the termination codon of the BRI gene. The mutant gene encodes BRI-L, the precursor of ABri peptides that accumulate in amyloid deposits in FBD brain. We now report that both BRI-L and its wild-type counterpart, BRI, were constitutively processed by the proprotein convertase, furin, resulting in the secretion of carboxyl-terminal peptides that encompass all or part of ABri. Elevated levels of peptides were generated from the mutant BRI precursor. Electron microscopic studies revealed that synthetic ABri peptides assembled into irregular, short fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates fibrillogenic peptides that initiate the pathogenesis of FBD.