Li Wenxue, West Neva, Colla Emanuela, Pletnikova Olga, Troncoso Juan C, Marsh Laura, Dawson Ted M, Jäkälä Pekka, Hartmann Tobias, Price Donald L, Lee Michael K
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2162-7. doi: 10.1073/pnas.0406976102. Epub 2005 Jan 31.
Abnormal biology of alpha-synuclein (alpha-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other alpha-synucleinopathies. Herein, we demonstrate that C-terminally truncated alpha-Syn (alpha-SynDeltaC), enriched in the pathological alpha-Syn aggregates, is normally generated from full-length alpha-Syn independent of alpha-Syn aggregation in brains and in cultured cells. The accumulation of alpha-SynDeltaC is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant alpha-Syn is associated with the enhanced cellular accumulation of alpha-SynDeltaC. Moreover, substoichiometric amounts of alpha-SynDeltaC enhance the in vitro aggregation of the more abundant full-length alpha-Syn. Finally, cases of alpha-synucleinopathy exhibit increases in the total soluble alpha-Syn and a higher proportion of soluble alpha-SynDeltaC, a condition favoring the aggregation of alpha-Syn. Collectively, our results indicate that the biology behind the generation and accumulation of alpha-SynDeltaC is likely to have relevance for the initiation and the progression of alpha-Syn aggregation in vivo.
α-突触核蛋白(α-Syn)的异常生物学特性直接与帕金森病及其他α-突触核蛋白病的发病机制相关。在此,我们证明,在病理性α-Syn聚集体中富集的C端截短型α-Syn(α-SynDeltaC)通常由全长α-Syn产生,与大脑和培养细胞中的α-Syn聚集无关。与非神经元细胞相比,α-SynDeltaC在神经元细胞中的积累增强。值得注意的是,家族性帕金森病相关突变型α-Syn的表达与α-SynDeltaC在细胞内的积累增强有关。此外,亚化学计量的α-SynDeltaC会增强更丰富的全长α-Syn的体外聚集。最后,α-突触核蛋白病病例显示总可溶性α-Syn增加,且可溶性α-SynDeltaC的比例更高,这种情况有利于α-Syn的聚集。总体而言,我们的结果表明,α-SynDeltaC产生和积累背后的生物学特性可能与体内α-Syn聚集的起始和进展相关。