期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 38, 页码 E3976-E3985出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1411694111
关键词
aging; lipid disequilibrium; proteinopathy
资金
- National Institutes of Neurological Disorders and Stroke [NS057656, NS075684]
Phosphatidylserine decarboxylase, which is embedded in the inner mitochondrial membrane, synthesizes phosphatidylethanolamine (PE) and, in some cells, synthesizes the majority of this important phospholipid. Normal levels of PE can decline with age in the brain. Here we used yeast and worms to test the hypothesis that low levels of PE alter the homeostasis of the Parkinson disease-associated protein alpha-synuclein (alpha-syn). In yeast, low levels of PE in the phosphatidylserine decarboxylase deletion mutant (psd1 Delta) cause decreased respiration, endoplasmic reticulum (ER) stress, a defect in the trafficking of the uracil permease, alpha-syn accumulation and foci, and a slow growth phenotype. Supplemental ethanolamine (ETA), which can be converted to PE via the Kennedy pathway enzymes in the ER, had no effect on respiration, whereas, in contrast, this metabolite partially eliminated ER stress, decreased alpha-syn foci formation, and restored growth close to that of wild-type cells. In Caenorhabditis elegans, RNAi depletion of phosphatidylserine decarboxylase in dopaminergic neurons expressing alpha-syn accelerates neurodegeneration, which supplemental ETA rescues. ETA fails to rescue this degeneration in worms that undergo double RNAi depletion of phosphatidylserine decarboxylase (psd-1) and choline/ETA phosphotransferase (cept-1), which encodes the last enzyme in the CDP-ETA Kennedy pathway. This finding suggests that ETA exerts its protective effect by boosting PE through the Kennedy pathway. Overall, a low level of PE causes ER stress, disrupts vesicle trafficking, and causes alpha-syn to accumulate; such cells likely die from a combination of ER stress and excessive accumulation of alpha-syn.
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