文章基本信息

标题：Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice
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作者：Michael K. Lee ; Wanda Stirling ; Yanqun Xu 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：2002
卷号：99
期号：13
页码：8968-8973
DOI：10.1073/pnas.132197599
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Mutations in -synuclein (-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, -Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of -Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 [->] Pro (A30P) or Ala-53 [->] Thr (A53T) human -Syns. The mice expressing the A53T human -Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of -Syn and ubiquitin. Consistent with abnormal neuronal accumulation of -Syn, brain regions with pathology exhibit increases in detergent-insoluble -Syn and -Syn aggregates. Our results demonstrate that the A53T mutant -Syn causes significantly greater in vivo neurotoxicity as compared with other -Syn variants. Further, -Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble -Syn.