Role of arginylation in prevention of alpha synuclein-driven neurodegeneration

精氨酸化在预防 α 突触核蛋白驱动的神经变性中的作用

• 批准号: 9910470
• 负责人: Anna S Kashina
• 金额: $ 52.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910470
• 关键词: Affect; Age; American; Animal Model; Brain; Cells; Data; Development; Disease; FYN gene; Family; Future; Goals; Healthcare; Homeostasis; Human; Impairment; In Vitro; Knock-out; Knockout Mice; Lewy Bodies; Link; Molecular; Multiple System Atrophy; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Post-Translational Protein Processing; Prevention; Proteins; Quality of life; Regulation; Research; Role; Sampling; Site; Symptoms; Testing; Therapeutic; Transgenic Mice; Work; alpha synuclein; cost; diagnostic biomarker; disease diagnosis; dopaminergic neuron; insight; mouse model; neurodegenerative phenotype; neuron loss; neuropathology; novel; novel diagnostics; outcome forecast; overexpression; prevent; prion-like; protein protein interaction; proteostasis; synucleinopathy; tool

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.

神经退行性疾病每年影响约 5000 万美国人，显着降低了生活质量 影响患者及其家人的生命，并花费数千亿美元的医疗费用。中的一个 神经退行性疾病的核心参与者是 α 突触核蛋白 (a-syn)，它是路易体的主要成分 帕金森病 (PD) 患者。异常的 a-syn 折叠与多种形式的 神经变性，最近被证明会导致自我传播的朊病毒样作用，从而导致多个系统 人类萎缩（MSA）。虽然许多因素被认为导致不同的a-syn错误折叠 疾病中，触发 a-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 会经历精氨酸化，这是一种新兴的 最近证明翻译后修饰对于蛋白质稳态和蛋白质-蛋白质至关重要 互动。我们发现精氨酸化可以防止 a-syn 在神经元中的病理性聚集 大脑中缺乏精氨酰转移酶 Ate1 的转基因小鼠会出现神经退行性疾病的症状。 与这些数据一致的是，人类 PD 患者的 Ate1 表达明显丧失 多巴胺能神经元。这些结果推动了我们的中心假设：a-syn 精氨酸化促进 正常的 a-syn 稳态，缺乏 a-syn 精氨酸化会导致异常的 a-syn 积累 从而促进神经退行性变。我们将通过以下一组综合测试这个假设 基于我们合作研究团队的多元化专业知识的具体目标：1）测试 a-syn 的作用 精氨酸化对神经元 a-syn 聚集和神经病理学的调节； 2）揭示角色 小鼠模型神经变性中的精氨酸化； 3) 建立精氨酸化之间的机制联系， a-syn 和人类患者的 PD 病理学。总之，所提出的工作将描述一种新型分子 可能是 PD 和 a-syn 依赖性神经变性的潜在机制，并将开发新的 PD诊断和治疗的途径。