The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson's disease
The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson's disease
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DOI：
10.1016/s0896-6273(03)00024-2
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发表时间：
2003-02-20
期刊：
影响因子：
16.2
通讯作者：
Selkoe, DJ
中科院分区：
文献类型：
--
作者：
Sharon, R;Bar-Joseph, I;Selkoe, DJ
错误折叠的蛋白质作为不溶性聚集体的积累发生在几种神经退行性疾病中。在帕金森病（PD）和路易体痴呆（DLB）中，α-突触核蛋白（α S）在不溶性内含物中积累。为了鉴定在不溶性聚集体之前的可溶性α S寡聚体，我们探测了中脑神经元（MES）细胞、正常和α S转基因小鼠脑以及正常、PD和DLB人脑的胞质溶胶。所有含有高度可溶性的低聚物;其检测通过脱脂增强的α S。多不饱和脂肪酸（PUFAs）的生活MES神经元的暴露增加了α S寡聚体水平，而饱和脂肪酸降低它们。PUFA直接促进重组α S的寡聚化。随着年龄的增长，转基因小鼠积累可溶性寡聚体。PD和DLB脑中可溶性脂质依赖性寡聚体的含量升高。我们的结论是，α S与PUFA在体内相互作用，以促进高度可溶性的低聚物的形成之前，不溶性的α S聚集体与神经变性。
Accumulation of misfolded proteins as insoluble aggregates occurs in several neurodegenerative diseases. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), alpha-synuclein (alphaS) accumulates in insoluble inclusions. To identify soluble alphaS oligomers that precede insoluble aggregates, we probed the cytosols of mesencephalic neuronal (MES) cells, normal and alphaS-transgenic mouse brains, and normal, PD, and DLB human brains. All contained highly soluble oligomers; of alphaS whose detection was enhanced by delipidation. Exposure of living MES neurons to polyunsaturated fatty acids (PUFAs) increased alphaS oligomer levels, whereas saturated FAs decreased them. PUFAs directly promoted oligomerization of recombinant alphaS. Transgenic mice accumulated soluble oligomers with age. PD and DLB brains had elevated amounts of the soluble, lipid-dependent oligomers. We conclude that alphaS interacts with PUFAs in vivo to promote the formation of highly soluble oligomers that precede the insoluble alphaS aggregates associated with neurodegeneration.