Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation.
Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation.
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发表时间：
2004
影响因子：
5.3
通讯作者：
P. Kotzbauer;B. Giasson;Alexxai V. Kravitz;L. Golbe;M. Mark;J. Trojanowski;V. Lee
中科院分区：
文献类型：
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作者：
P. Kotzbauer;B. Giasson;Alexxai V. Kravitz;L. Golbe;M. Mark;J. Trojanowski;V. Lee
α-突触核蛋白 (α-syn) 基因突变导致罕见的家族性帕金森综合征，这一发现导致对散发性帕金森病 (PD) 和其他神经退行性疾病中 α-syn 结构改变的广泛表征。我们在此报告一例具有 A53T α-syn 基因突变的家族性 PD 病例的 α-syn 神经病理学的免疫组织化学、生化和超微结构特征。在几乎所有检查的大脑区域中都检测到不溶性丝状 α-syn 病变，与散发性 PD 一样，我们观察到在这种家族性疾病中不溶性硝化 α-syn 积累。在该患者的一些大脑区域中也检测到丝状不溶性 tau 蛋白的显着积累，表明 A53T 突变体 α-syn 在 tau 纤维化中发挥作用。事实上，tau 和 alpha-syn 原纤维化的体外研究表明，A53T 突变加速了 alpha-syn 原纤维的形成，启动 tau 组装成丝，并协同增强 tau 和 alpha-syn 的原纤维化。我们的数据表明 α-syn 和 tau 蛋白纤维化与 PD 发病机制有关，并表明不同的淀粉样蛋白可能在神经退行性疾病中相互交叉传播。
Mutations in the alpha-synuclein (alpha-syn) gene are responsible for a rare familial parkinsonism syndrome, a finding that has led to extensive characterization of altered alpha-syn structure in sporadic Parkinson's disease (PD) and other neurodegenerative disorders. We report here the immunohistochemical, biochemical and ultrastructural characterization of alpha-syn neuropathology in a case of familial PD with the A53T alpha-syn gene mutation. Insoluble filamentous alpha-syn lesions were detected in almost all brain regions examined and as in sporadic PD, we observed the accumulation of insoluble nitrated alpha-syn in this familial disorder. Significant accumulations of filamentous insoluble tau protein also were detected in some brain regions of this patient, suggesting a role for A53T mutant alpha-syn in tau fibrillization. Indeed, in vitro studies of tau and alpha-syn fibrillization showed that the A53T mutation accelerated alpha-syn fibril formation, initiated tau assembly into filaments and synergistically enhanced fibrillization of both tau and alpha-syn. Our data implicate fibrillization of alpha-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases.