Saha Anirban R, Hill Josephine, Utton Michelle A, Asuni Ayodeji A, Ackerley Steven, Grierson Andrew J, Miller Christopher C, Davies Alun M, Buchman Vladimir L, Anderton Brian H, Hanger Diane P
Department of Neuroscience, PO Box 38, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK.
J Cell Sci. 2004 Mar 1;117(Pt 7):1017-24. doi: 10.1242/jcs.00967.
Alpha-synuclein is a major protein constituent of Lewy bodies and mutations in alpha-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation of perikaryal and neuritic aggregates of alpha-synuclein, which is a presynaptic protein, is that the mutations disrupt alpha-synuclein transport and lead to its proximal accumulation. We found that mutant forms of alpha-synuclein, either associated with Parkinson's disease (A30P or A53T) or mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal transport following transfection into cultured neurons. Furthermore, transfection of A30P, but not wild-type, alpha-synuclein results in accumulation of the protein proximal to the cell body. We propose that the reduced axonal transport exhibited by the Parkinson's disease-associated alpha-synuclein mutants examined in this study might contribute to perikaryal accumulation of alpha-synuclein and hence Lewy body formation and neuritic abnormalities in diseased brain.
α-突触核蛋白是路易小体的主要蛋白质成分，α-突触核蛋白的突变会导致家族性常染色体显性帕金森病。α-突触核蛋白是一种突触前蛋白，其在胞体和神经突中形成聚集体的一种解释是，突变破坏了α-突触核蛋白的转运并导致其在近端积累。我们发现，与帕金森病相关的（A30P或A53T）α-突触核蛋白突变体形式，或模拟特定丝氨酸而非酪氨酸磷酸化状态的突变体形式，在转染到培养神经元后轴突运输减少。此外，转染A30Pα-突触核蛋白（而非野生型）会导致该蛋白在细胞体近端积累。我们提出，本研究中检测的与帕金森病相关的α-突触核蛋白突变体所表现出的轴突运输减少，可能导致α-突触核蛋白在胞体积累，进而导致患病大脑中路易小体形成和神经突异常。
