Cleavage of α-synuclein by calpain:: Potential role in degradation of fibrillized and nitrated species of α-synuclein
Cleavage of α-synuclein by calpain:: Potential role in degradation of fibrillized and nitrated species of α-synuclein
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DOI：
10.1021/bi047846q
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发表时间：
2005-05-31
期刊：
影响因子：
2.9
通讯作者：
Lynch, DR
中科院分区：
文献类型：
--
作者：
Mishizen-Eberz, AJ;Norris, EH;Lynch, DR
α-突触核蛋白 (alpha-syn) 是帕金森病和相关神经退行性疾病（称为突触核蛋白病）的神经病理学标志的主要蛋白质成分。 α-syn 纤维化的机制和 α-syn 的降解过程均尚未阐明。此前，我们在体外证明野生型、突变型和纤维状 α-syn 蛋白是钙蛋白酶 I 的底物。在这项研究中，我们证明钙蛋白酶介导的在可溶性α-syn的中间区域附近和中间区域内的裂解（有/没有酪氨酸硝化和氧化）会产生无法自纤维化的片段。更重要的是，这些片段可以防止全长 α-syn 纤维化。钙蛋白酶介导的由野生型或硝化 α-syn 组成的 α-syn 原纤维的裂解产生 C 末端截短的片段，保留其原纤维结构并诱导可溶性全长 α-syn 共组装。因此，钙蛋白酶裂解的可溶性α-syn抑制原纤维化，而钙蛋白酶裂解的原纤维a-syn促进进一步的共组装。这些结果提供了对突触核蛋白病潜在疾病机制的深入了解，因为α-突触核原纤维的形成可能与这些疾病的发作/进展存在因果关系。
alpha-Synuclein (alpha-syn) is a major protein component of the neuropathological hallmarks of Parkinson's disease and related neurodegenerative disorders termed synucleinopathies. Neither the mechanism of alpha-syn fibrillization nor the degradative process for alpha-syn has been elucidated. Previously, we showed that wild-type, mutated, and fibrillar alpha-syn proteins are substrates of calpain I in vitro. In this study, we demonstrate that calpain-mediated cleavage near and within the middle region of soluble alpha-syn with/without tyrosine nitration and oxidation generates fragments that are unable to self-fibrillize. More importantly, these fragments prevent full-length alpha-syn from fibrillizing. Calpain-mediated cleavage of alpha-syn fibrils composed of wild-type or nitrated alpha-syn generate C-terminally truncated fragments that retain their fibrillar structure and induce soluble full-length alpha-syn to co-assemble. Therefore, calpain-cleaved soluble alpha-syn inhibits fibrillization, whereas calpain-cleaved fibrillar a-syn promotes further co-assembly. These results provide insight into possible disease mechanisms underlying synucleinopathies since the formation of alpha-syn fibrils could be causally linked to the onset/progression of these disorders.