文章基本信息

标题：Positive and negative regulation of APP amyloidogenesis by sumoylation
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作者：Yonghong Li ; Hui Wang ; Su Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：1
页码：259-264
DOI：10.1073/pnas.0235361100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Amyloid {beta} peptide (A{beta}) generated from amyloid precursor protein (APP) is central to Alzheimer's disease (AD). Signaling pathways affecting APP amyloidogenesis play critical roles in AD pathogenesis and can be exploited for therapeutic intervention. Here, we show that sumoylation, covalent modification of cellular proteins by small ubiquitin-like modifier (SUMO) proteins, regulates A{beta} generation. Increased protein sumoylation resulting from overexpression of SUMO-3 dramatically reduces A{beta} production. Conversely, reducing endogenous protein sumoylation with dominant-negative SUMO-3 mutants significantly increases A{beta} production. We also show that mutant SUMO-3, K11R, which can only be monomerically conjugated to target proteins, has an opposite effect on A{beta} generation to that by SUMO-3, which can form polymeric chains on target proteins. In addition, SUMO-3 immunoreactivity is predominantly detected in neurons in brains from AD, Down's syndrome, and nondemented humans. Therefore, polysumoylation reduces whereas monosumoylation or undersumoylation enhances A{beta} generation. These findings provide a regulatory mechanism in APP amyloidogenesis and suggest that components in the sumoylation pathway may be critical in AD onset or progression.