Liu Chang-Wei, Giasson Benoit I, Lewis Karen A, Lee Virginia M, Demartino George N, Thomas Philip J
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
J Biol Chem. 2005 Jun 17;280(24):22670-8. doi: 10.1074/jbc.M501508200. Epub 2005 Apr 19.
Parkinson disease and other alpha-synucleinopathies are characterized by the deposition of intraneuronal alpha-synuclein (alphaSyn) inclusions. A significant fraction (about 15%) of alphaSyn in these pathological structures are truncated forms that have a much higher propensity than the full-length alphaSyn to form aggregates in vitro. However, little is known about the role of truncated alphaSyn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated alphaSyns induce rapid aggregation of full-length protein at substoichiometric ratios. Co-overexpression of truncated alphaSyn with full-length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated alphaSyn in the pathogenesis of diseases involving alphaSyn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble alphaSyns that correlates with the onset of pathology in transgenic mice expressing human alphaSyn-A53T mutant. The caspase-like activity of the 20 S proteasome produces truncated fragments similar to those found in patients and animal models from degradation of unstructured alphaSyn. We propose a model in which incomplete degradation of alphaSyn, especially under overloaded proteasome capacity, produces highly amyloidogenic fragments that rapidly induce the aggregation of full-length protein. These aggregates in turn reduce proteasome activity, leading to further accumulation of fragmented and full-length alphaSyns, creating a vicious cycle of cytotoxicity. This model has parallels in other neurodegenerative diseases, such as Huntington disease, where coaggregation of poly(Q) fragments with full-length protein has been observed.
帕金森病和其他α-突触核蛋白病的特征是神经元内α-突触核蛋白（αSyn）包涵体的沉积。在这些病理结构中，相当一部分（约15%）的αSyn是截短形式，与全长αSyn相比，它们在体外形成聚集体的倾向要高得多。然而，关于截短的αSyn物种在发病机制中的作用或其产生方式知之甚少。在这里，我们提供了一项体外机制研究，证明截短的αSyns以亚化学计量比诱导全长蛋白快速聚集。截短的αSyn与全长蛋白共过表达会增加多巴胺能SH-SY5Y细胞对氧化应激的易感性。这些结果表明截短的αSyn在涉及αSyn聚集的疾病发病机制中起促发作用。在这方面，在一些家族性帕金森病病例中发现的A53T突变加剧了不溶性αSyns的积累，这与表达人αSyn-A53T突变体的转基因小鼠的病理发作相关。20S蛋白酶体的半胱天冬酶样活性从无结构的αSyn降解产生与患者和动物模型中发现的类似的截短片段。我们提出了一个模型，其中αSyn的不完全降解，特别是在蛋白酶体能力过载的情况下，产生高度淀粉样生成的片段，这些片段迅速诱导全长蛋白聚集。这些聚集体反过来又降低了蛋白酶体活性，导致截短和全长αSyns的进一步积累，形成细胞毒性的恶性循环。这个模型在其他神经退行性疾病中也有类似情况，比如亨廷顿病，在那里已经观察到多聚谷氨酰胺片段与全长蛋白的共聚集。
