Biomedical Research Foundation of Academy of Athens, Athens, Greece.
Lancet Neurol. 2011 Nov;10(11):1015-25. doi: 10.1016/S1474-4422(11)70213-7.
Substantial genetic, neuropathological, and biochemical evidence implicates the presynaptic neuronal protein α-synuclein in Parkinson's disease and related Lewy body disorders. How dysregulation of α-synuclein leads to neurodegeneration is, however, unclear. Soluble oligomeric, but not fully fibrillar, α-synuclein is thought to be toxic. The major neuronal target of aberrant α-synuclein might be the synapse. The effects of aberrant α-synuclein might include alteration of calcium homoeostasis or mitochondrial fragmentation and, in turn, mitochondrial dysfunction, which could link α-synuclein dysfunction to recessive and toxin-induced parkinsonism. α-Synuclein also seems to be linked to other genetic forms of Parkinson's disease, such as those linked to mutations in GBA or LRRK2, possibly through common effects on autophagy and lysosomal function. Finally, α-synuclein is physiologically secreted, and this extracellular form could lead to the spread of pathological accumulations and disease progression. Consequently, factors that regulate the levels, post-translational modifications, specific aberrant cellular effects, or secretion of α-synuclein might be targets for therapy.
大量的遗传学、神经病理学和生物化学证据表明，突触前神经元蛋白α-突触核蛋白与帕金森病和相关路易体障碍有关。然而，α-突触核蛋白失调如何导致神经退行性变尚不清楚。可溶性寡聚体，但不是完全纤维状的α-突触核蛋白被认为是有毒的。异常α-突触核蛋白的主要神经元靶标可能是突触。异常α-突触核蛋白的作用可能包括钙动态平衡或线粒体片段化的改变，进而导致线粒体功能障碍，这可能将α-突触核蛋白功能障碍与隐性和毒素诱导的帕金森病联系起来。α-突触核蛋白似乎也与其他形式的帕金森病有关，如与 GBA 或 LRRK2 突变相关的帕金森病，可能是通过对自噬和溶酶体功能的共同影响。最后，α-突触核蛋白在生理上被分泌，这种细胞外形式可能导致病理性积累和疾病进展的传播。因此，调节α-突触核蛋白水平、翻译后修饰、特定异常细胞作用或分泌的因素可能是治疗的靶点。
