A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation -: Implications for pathogenesis of Parkinson disease
A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation -: Implications for pathogenesis of Parkinson disease
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DOI：
10.1074/jbc.m501508200
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发表时间：
2005-06-17
影响因子：
4.8
通讯作者：
Thomas, PJ
中科院分区：
文献类型：
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作者：
Liu, CW;Giasson, BI;Thomas, PJ
帕金森病和其他α-突触核蛋白病的特征在于神经元内α-突触核蛋白（α-Syn）内含物的沉积。在这些病理结构中，α Syn的显著部分（约15%）是截短形式，其具有比全长α Syn高得多的体外形成聚集体的倾向。然而，关于截短的α-Syn物种在发病机制中的作用或它们产生的方式知之甚少。在此，我们提供了体外机制研究，证明截短的α-Syn以亚化学计量比诱导全长蛋白质的快速聚集。截短的aSyn与全长蛋白质的共过表达增加多巴胺能SH-SY 5 Y细胞中对氧化应激的细胞脆弱性。这些结果表明截短的α-Syn在涉及α-Syn聚集的疾病的发病机制中的促发作用。在这方面，在家族性帕金森病的一些病例中发现的A53 T突变加剧了不溶性α Syn的积累，这与表达人α Syn-A53 T突变体的转基因小鼠中的病理学发作相关。20 S蛋白酶体的半胱天冬酶样活性产生截短片段，类似于患者和动物模型中非结构化α Syn降解产生的截短片段。我们提出了一个模型，其中α-Syn的不完全降解，特别是在超负荷的蛋白酶体能力下，产生高度淀粉样蛋白生成的片段，这些片段迅速诱导全长蛋白质的聚集。这些聚集体反过来降低蛋白酶体活性，导致片段化和全长α-Syn的进一步积累，产生细胞毒性的恶性循环。该模型在其他神经变性疾病中具有相似之处，例如亨廷顿病，其中已经观察到聚（Q）片段与全长蛋白质的共聚集.
Parkinson disease and other alpha-synucleinopathies are characterized by the deposition of intraneuronal alpha-synuclein (alpha Syn) inclusions. A significant fraction (about 15%) of alpha Syn in these pathological structures are truncated forms that have a much higher propensity than the full-length alpha Syn to form aggregates in vitro. However, little is known about the role of truncated alpha Syn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated alpha Syns induce rapid aggregation of full- length protein at sub-stoichiometric ratios. Co-overexpression of truncated alpha Syn with full- length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated alpha Syn in the pathogenesis of diseases involving alpha Syn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble alpha Syns that correlates with the onset of pathology in transgenic mice expressing human alpha Syn-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 alpha Syn. We propose a model in which incomplete degradation of alpha Syn, 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 alpha Syns, 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.