Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany.
Ann Neurol. 2013 Jul;74(1):109-18. doi: 10.1002/ana.23905. Epub 2013 Aug 6.
Whereas the contribution of α-synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, β-synuclein, is enigmatic. β-Synuclein is widely expressed throughout the central nervous system, as is α-synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that β-synuclein can act as an ameliorating regulator of α-synuclein-induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being nonaggregating due to the absence of most of the aggregation-promoting NAC domain. However, a mutation of β-synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of β-synuclein has been demonstrated in vitro.
Neurotoxicity and aggregation properties of α-, β-, and γ-synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons.
Supporting the hypothesis that β-synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type β-synuclein is neurotoxic for cultured primary neurons. Furthermore, β-synuclein formed proteinase K-resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of β-synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria nonfunctional in terms of ion handling and respiration even at late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by α-, β-, and γ-synuclein revealed that β-synuclein was eventually as neurotoxic as α-synuclein for nigral dopaminergic neurons, whereas γ-synuclein proved to be nontoxic and had very low aggregation propensity.
Our results suggest that the role of β-synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited.
虽然 α-突触核蛋白在帕金森病中的神经退行性作用已被广泛接受，但与其密切同源物 β-突触核蛋白的潜在作用仍不清楚。β-突触核蛋白与 α-突触核蛋白广泛表达于中枢神经系统，但这两种蛋白质的生理功能仍不清楚。最近的研究结果支持这样一种观点，即β-突触核蛋白可以作为一种改善 α-突触核蛋白诱导的神经毒性的调节剂，具有神经保护作用而不是神经退行性作用，并且由于缺乏大多数促进聚集的 NAC 结构域，它不会聚集。然而，与路易体痴呆相关的 β-突触核蛋白突变使该蛋白在转基因小鼠中具有神经毒性，并且体外已经证明了 β-突触核蛋白的纤维形成。
在大鼠黑质纹状体投射和培养神经元中比较阐明了 α-、β-和 γ-突触核蛋白的神经毒性和聚集特性。
支持β-突触核蛋白可以作为神经退行性变诱导因素的假说，我们证明野生型β-突触核蛋白对培养的原代神经元具有神经毒性。此外，β-突触核蛋白在体内形成多巴胺能神经元中蛋白水解酶抗性聚集体，导致大鼠中明显且进行性的神经退行性变。β-突触核蛋白的表达导致线粒体片段化，但即使在神经退行性变的晚期，这种片段化也不会使线粒体在离子处理和呼吸方面失去功能。比较 α-、β-和 γ-突触核蛋白诱导的神经退行性效应表明，β-突触核蛋白最终对黑质多巴胺能神经元的神经毒性与 α-突触核蛋白一样，而 γ-突触核蛋白则被证明是无毒的，且聚集倾向非常低。
我们的结果表明，β-突触核蛋白作为帕金森病和路易体痴呆等聚集病中神经病理学潜在调节剂的作用需要重新审视。
