期刊
NATURE NEUROSCIENCE
卷 12, 期 9, 页码 1129-U13出版社
NATURE RESEARCH
DOI: 10.1038/nn.2372
关键词
-
资金
- Parkinson's Disease Society UK [G-4063, G-0713, G-0715]
- Royal Society and Wellcome Trust [081987]
- MRC Centre for Developmental and Biomedical Genetics [G070091]
- Wellcome Trust [GR077544AIA]
- Light Microscopy Facility
- Medical Research Council [G0700091B] Funding Source: researchfish
- Parkinson"
- s UK [G-0715, G-0713] Funding Source: researchfish
Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据