文章基本信息

标题：Polyamine pathway contributes to the pathogenesis of Parkinson disease
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作者：Nicole M. Lewandowski ; Shulin Ju ; Miguel Verbitsky 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：2010
卷号：107
期号：39
页码：16970-16975
DOI：10.1073/pnas.1011751107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and {alpha}-synuclein toxicity, we investigated a yeast model expressing {alpha}-synuclein. Polyamines were found to enhance the toxicity of {alpha}-synuclein, and an unbiased genome-wide screen for modifiers of {alpha}-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing {alpha}-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.
关键词：functional MRI ; SAT1 ; brainstem