Role of arginylation in prevention of alpha synuclein-driven neurodegeneration

据估计，每年有5000万美国人受到神经退行性疾病的影响，显著降低了 患者及其家人的生命，并在医疗保健方面花费了数千亿美元。其中一个 神经退行性变的核心是α-突触核蛋白(a-syn)，它是路易小体的主要成分。 在帕金森氏病(PD)患者中。异常的a-syn折叠与多种形式的 神经退行性变，最近被证明导致自我传播的类病毒作用，导致多系统 人类的萎缩(MSA)。虽然许多因素被认为是导致a-syn错误折叠的不同因素 疾病，触发-SYN从正常状态向病理状态转变的机制尚不清楚。 我们的初步数据表明，正常大脑中的a-syn经历了精氨酸化，这是一种新兴的 翻译后修饰是蛋白质动态平衡和蛋白质-蛋白质相互作用的关键 互动。我们发现精氨酸化可以阻止a-syn在神经元中的病理性聚集，并且 大脑中缺乏精氨酸基转移酶ATE1的转基因小鼠会出现神经退化的症状。 与这些数据一致的是，人类帕金森病患者表现出显著且显著的Ate1表达缺失 多巴胺能神经元。这些结果推动了我们的中心假设，即a-syn精氨酸化有助于 正常a-syn动态平衡和缺乏a-syn精氨酸化会导致a-syn异常堆积 从而促进神经退化。我们将通过以下一组集成的 将建立在我们合作研究团队的不同专业知识基础上的具体目标：1)测试a-syn的作用 精氨酸化在调节神经元α-syn聚集和神经病理中的作用；2)揭示 精氨酸化在小鼠神经变性模型中的作用；以及3)在精氨酸化、 A-SYN和帕金森病患者的病理改变。总之，这项拟议的工作将描述一种新的分子 帕金森病和α-突触蛋白依赖性神经变性的潜在机制，并将开发新的 帕金森病的诊断和治疗途径。

Neurodegeneration affects an estimated 50 million Americans each year, significantly reducing the quality of life for the patients and their families and costing hundreds of billions of dollars in health care. One of the central players in neurodegeneration is alpha synuclein (a-syn), the major component of the Lewy bodies seen in Parkinson's disease (PD) patients. Aberrant a-syn folding has been implicated in multiple forms of neurodegeneration and recently shown to result in self-propagating prion-like action causing multiple system atrophy (MSA) in humans. While numerous factors are believed to contribute to a-syn misfolding in different diseases, the mechanisms that trigger a-syn transition from a normal to pathological state are not understood. Our preliminary data demonstrate that a-syn in the normal brain undergoes arginylation, an emerging posttranslational modification recently shown to be essential for protein homeostasis and protein-protein interactions. We find that arginylation prevents the pathological aggregation of a-syn in neurons and that transgenic mice lacking arginyltransferase Ate1 in the brain develop symptoms of neurodegeneration. Consistent with these data, human PD patients show a pronounced and significant loss of Ate1 expression in dopaminergic neurons. These results drive our central hypothesis that a-syn arginylation facilitates normal a-syn homeostasis and that lack of a-syn arginylation leads to abnormal a-syn accumulation thereby promoting neurodegeneration. We will test this hypothesis through the following set of integrated specific aims that will build on the diverse expertise of our collaborative research team: 1) test the role of a-syn arginylation in regulation of a-syn aggregation and neuropathology in neurons; 2) uncover the role of arginylation in neurodegeneration in mouse models; and 3) establish a mechanistic link between arginylation, a-syn, and PD pathology in human patients. Together, the proposed work will characterize a novel molecular mechanism that potentially underlies PD and a-syn dependent neurodegeneration and will develop new avenues for PD diagnosis and treatment.