Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease
Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease
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DOI：
10.1016/j.nbd.2013.03.014
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发表时间：
2013-08-01
影响因子：
6.1
通讯作者：
Romero-Ramos, Marina
中科院分区：
文献类型：
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作者：
Febbraro, Fabia;Sahin, Gurdal;Romero-Ramos, Marina
丝氨酸129位的α-突触核蛋白(S129)在帕金森病患者中高度升高，主要聚集在路易小体。几个小组使用重组腺相关病毒(RAAV)载体研究了α-突触核蛋白中S129的磷酸化在帕金森病大鼠模型中的作用。结果是不一致的，因此S129的磷酸化在α-突触核蛋白毒性中的作用尚不清楚。这促使我们在体内重新检查S129修饰的α-突触核蛋白物种的神经病理和行为效应。为此，我们使用了两种突变形式的人α-突触核蛋白，其中S129被丙氨酸(S129A)取代以阻断磷酸化，或者被天冬氨酸(S129D)取代以模拟磷酸化，并将它们与野生型α-突触核蛋白进行比较。这种方法在设计上与以前的研究相似，但我们对多巴胺能变性的调查还包括对α-突触核蛋白在纹状体中诱导的病理进行详细研究，并分析运动障碍。我们的结果表明，与S129Aα-突触核蛋白相比，过度表达S129D或野生型α-突触核蛋白会加速多巴胺能纤维的丢失。此外，在接受突变体S129Dα-突触核蛋白治疗的组中，出现运动障碍的时间早于其他两种形式的α-突触核蛋白。相反，与其他两种形式的α-突触核蛋白相比，S129Aα-突触核蛋白显示出明显更大的病理性α-突触核蛋白阳性包涵体，以及更慢的多巴胺能纤维丢失，这表明该突变具有神经保护作用。长期观察时，三种α-突触核蛋白均可导致纹状体纤维中α-突触核蛋白的病理性堆积和黑质多巴胺能细胞死亡。我们的数据显示，α-突触核蛋白S129残基的变化影响了病理和神经退行性变的速度，总体上是有害的，将S129改变为模拟其磷酸化状态的残基。(C)2013 Elsevier Inc.保留所有权利。
Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in alpha-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in alpha-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified alpha-synuclein species in vivo. For this purpose, we used two mutated forms of human alpha-synuclein in which the S129 was replaced either with an alanine (S129A), to block phosphorylation, or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild type alpha-synuclein. This approach was similar in design to previous studies, however our investigation of dopaminergic degeneration also included performing a detailed study of the alpha-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type alpha-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A alpha-synuclein. Furthermore, the motor deficit seen in the group treated with the mutant S129D alpha-synuclein appeared earlier than the other two forms of alpha-synuclein. Conversely, S129A alpha-synuclein showed significantly larger pathological alpha-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of alpha-synuclein, suggesting a neuroprotective effect of the mutation. When examined at long-term, all three alpha-synuclein forms resulted in pathological accumulations of alpha-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra. Our data show that changes in the S129 residue of alpha-synuclein influence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state. (c) 2013 Elsevier Inc. All rights reserved.