Role of arginylation in prevention of alpha synuclein-driven neurodegeneration

神经退行性疾病每年影响约5000万美国人，大大降低了生活质量。 病人和他们的家人的生命，花费数千亿美元的医疗保健。之一 神经退行性变的主要参与者是α-突触核蛋白（α-syn），它是路易体的主要成分 帕金森病（PD）患者。异常的α-syn折叠涉及多种形式的 神经变性，最近显示导致自传播朊病毒样作用，引起多个系统 萎缩症（MSA）。虽然许多因素被认为有助于不同细胞中的a-syn错误折叠， 尽管α-syn在疾病中的作用是非常重要的，但是触发α-syn从正常状态转变为病理状态的机制尚不清楚。 我们的初步数据表明，正常大脑中的a-syn经历了乙酰化，这是一种新兴的 翻译后修饰最近被证明是蛋白质稳态和蛋白质-蛋白质 交互.我们发现，腺苷酸化阻止了神经元中a-syn的病理性聚集， 脑中缺乏乙酰转移酶Ate 1的转基因小鼠出现神经变性的症状。 与这些数据一致，人类PD患者在帕金森病中表现出Ate 1表达的明显和显著损失。 多巴胺能神经元这些结果推动了我们的中心假设，即α-syn-酰基化促进了 正常的α-syn体内平衡和缺乏α-syn乙酰化导致异常的α-syn积累 从而促进神经变性。我们将通过以下一组综合数据来检验这一假设。 具体目标将建立在我们合作研究团队的各种专业知识基础上：1）测试a-syn的作用 乙酰化在调节神经元中的a-syn聚集和神经病理学中的作用; 2）揭示乙酰化在神经元中的作用。 小鼠模型中神经变性中的腺苷酸化;和3）在腺苷酸化， a-syn和人类患者中的PD病理学。总之，拟议的工作将表征一种新的分子 这可能是PD和α-syn依赖性神经变性的基础机制，并将开发新的 PD诊断和治疗的途径。

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.