期刊
JOURNAL OF NEUROCHEMISTRY
卷 119, 期 2, 页码 389-397出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07431.x
关键词
alpha-synuclein; membrane binding; N-terminus; Parkinson's disease; toxicity
资金
- Morris K. Udall Parkinson's Disease Research Center for Excellence [NS038375]
- MEFOPA [FP7-Health 2009 241791]
alpha-Synuclein causes Parkinson's disease if mutated or aberrantly produced in neurons. alpha-Synuclein-lipid interactions are important for the normal function of the protein, but can also contribute to pathogenesis. We previously reported that deletion of the first 10 N-terminal amino acids dramatically reduced lipid binding in vitro, as well as membrane binding and toxicity in yeast. Here we extend this study to human neuroblastoma SHSY-5Y cells, and find that in these cells the first 10 N-terminal residues do not affect alpha-synuclein membrane binding, self-association and cell viability, contrary to yeast. Differences in lipid composition, membrane fluidity and cytosolic factors between yeast and neuronal cells may account for the distinct binding behavior of the truncated variant in these two systems. Retinoic acid promotes differentiation and alpha-synuclein oligomer formation in neuroblastoma cells, while addition of a proteasomal inhibitor induces neurite outgrowth and toxicity to certain wild-type and truncated alpha-synuclein clones. Yeast recapitulate several features of alpha-synuclein (patho) biology, but its simplicity sets limitations; verification of yeast results in more relevant model systems is, therefore, essential.
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