Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B
Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
J Neurosci. 1999 Jul 15;19(14):5782-91. doi: 10.1523/JNEUROSCI.19-14-05782.1999.
alpha-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in alpha-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of alpha-synuclein inhibits protein kinase C activity. The association of alpha-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of alpha-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type alpha-synuclein is toxic, and overexpression of alpha-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha-synuclein suggests that it might act as a protein chaperone and that accumulation of alpha-synuclein could contribute to cell death in neurodegenerative diseases.
α-突触核蛋白与包括帕金森病（PD）和阿尔茨海默病在内的许多神经退行性疾病的病理生理学有关。α-突触核蛋白的突变导致一些家族性PD病例（Polymeropoulos等人，1997年；Kruger等人，1998年）。此外，许多神经退行性疾病在营养不良的神经突和路易小体中显示出α-突触核蛋白的积累（Spillantini等人，1998年）。在这里，我们表明α-突触核蛋白与14-3-3蛋白具有物理和功能同源性，14-3-3蛋白是一类普遍存在的细胞质伴侣蛋白家族。α-突触核蛋白和14-3-3蛋白的区域具有超过40%的同源性。此外，α-突触核蛋白与14-3-3蛋白以及一些已知与14-3-3相关的蛋白结合，包括蛋白激酶C、BAD和细胞外调节激酶，但不与Raf-1结合。我们还表明，α-突触核蛋白的过表达抑制蛋白激酶C活性。α-突触核蛋白与BAD的结合以及对蛋白激酶C的抑制表明，α-突触核蛋白表达增加可能是有害的。与这一假设一致，我们观察到野生型α-突触核蛋白的过表达是有毒的，而含有A53T或A30P突变的α-突触核蛋白的过表达表现出更大的毒性。α-突触核蛋白的活性和结合谱表明它可能作为一种蛋白伴侣发挥作用，并且α-突触核蛋白的积累可能导致神经退行性疾病中的细胞死亡。
