Mechanisms of Neurodegeneration in alpha-Synuclein Transgenic Mice

α-突触核蛋白转基因小鼠神经变性的机制

• 批准号: 7664242
• 负责人: Hanseok Ko
• 金额: $ 35.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664242
• 关键词: ABL1 gene; Adult; Affect; Alpha-Synuclein transgenic mouse; Attenuated; Biochemical; Brain; Cell Death; Centers of Research Excellence; Cessation of life; Chronic; Complex; Defect; Disease; Event; Exhibits; Functional disorder; Genetic; Human; Instruction; LRRK2 gene; Lead; Mitochondria; Modeling; Mus; Nerve Degeneration; Neurons; Onset of illness; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pattern; Phosphorylation; Process; Protein Tyrosine Kinase; Resources; Role; Severities; Stress; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Tyrosine Phosphorylation; alpha synuclein; c-abl Proto-Oncogenes; in vivo; mitochondrial dysfunction; mutant; novel therapeutic intervention; oxidative damage; parkin gene/protein; synuclein, alpha (non A4 component of amyloid precursor) protein, human

Project 2: Mechanisms of Neurodegeneration in alpha-Synuclein Transgenic Mice. While the causes of Parkinson's disease (PD) is not known, genetic and biochemical abnormalities of alpha- synuclein are directly implicated in the pathogenesis PD and other alpha-synucleinopathies. Transgenic (Tg) mice expressing the A53T mutant human alpha-synuclein develop adult-onset disease with a progressive motoric dysfunction leading to death. The affected mice exhibit many of the features of human alpha- synucleinopathies, including aberrant aggregation of a-Syn and neurodegeneration in subcortical regions. Characterization of alpha-synucleinopathy in Tg mice reveal signs of oxidative stress, including mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of PD and other a-synucleinopathies, we will examine the pathological relationships between oxidative stress and alpha-synucleinopathies in Hua-Syn Tg mice. First (Aim 1), we will determine whether the disease in the Tg mice is associated with oxidative stress, particularly associated with mitochondrial abnormalities. Second (Aims 2 and 3), we will test if oxidative stress act in concert with alpha-synuclein abnormalities exacerbate alpha-synuclein pathology and neurodegeneration. Finally, we hypothesize that oxidative stress causes activation of c-Abl and c-Abl activation directly participates in the disease. We will show that alpha-synuclein pathology is associated with c-Abl activation in mice and in human PD cases. We will show that lack of c-Abl function attenuates neurodegeneration in alpha-synuclein Tg mice. Finally, we will show that c-Abl phosphorylates alpha-synuclein and such alpha-synuclein is preferentially found associated with the aggregates. In addition, we will collaborate with Project 1 to determine if alpha- synuclein pathology leads to defects in parkin function and with Project 3 to determine linke between mutant LRRK2 and alpha-synuclein pathology in vivo. These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches. RELEVANCE (See instructions): Alpha-synuclein abnormalities are implicated as the events responsible for cell death in PD and other related diseases. Thus, understanding how alpha-synuclein abnormalities cause neuronal death in brain will provide better understanding about PD and may lead to therapeutic approaches that will target the underlying processes that are responsible for PD.

项目2：α-突触核蛋白转基因小鼠神经退行性变的机制。 虽然帕金森氏病（PD）的原因尚不清楚，但α-肾上腺素的遗传和生化异常可能是导致帕金森氏病的主要原因。 突触核蛋白直接参与PD和其他α-突触核蛋白病的发病机制。转基因（Tg） 表达A53 T突变体人α-突触核蛋白的小鼠发生成人发病疾病， 运动功能障碍导致死亡受影响的小鼠表现出许多人类阿尔法- 突触核蛋白病，包括α-Syn的异常聚集和皮质下区域的神经变性。 Tg小鼠中α-突触核蛋白病的特征揭示了氧化应激的迹象，包括线粒体 异常因为线粒体异常和氧化应激都与 帕金森病和其他α-突触核蛋白病的发病机制，我们将研究病理关系， Hua-Syn Tg小鼠中的氧化应激和α-突触核蛋白病。首先（目标1），我们将确定是否 Tg小鼠的疾病与氧化应激有关，特别是与线粒体 异常第二（目标2和3），我们将测试氧化应激是否与α-突触核蛋白协同作用 异常加剧α-突触核蛋白病理和神经变性。最后，我们假设 氧化应激引起c-Abl的活化，c-Abl的活化直接参与疾病。我们将 显示在小鼠和人PD病例中α-突触核蛋白病理与c-Abl活化相关。我们 将显示c-Abl功能的缺乏减弱了α-突触核蛋白Tg小鼠中的神经变性。最后我们 将显示c-Abl磷酸化α-突触核蛋白，并且这种α-突触核蛋白优先被发现 与聚集体相关。此外，我们将与项目1合作，以确定阿尔法- 突触核蛋白病理导致parkin功能缺陷，并与项目3一起确定突变体之间的联系 体内LRRK 2和α-突触核蛋白病理学。这些研究将提供体内实验测试， 与人类α-突触核蛋白病的发病机制直接相关并可能导致 新的治疗方法。 相关性（参见说明）： α-突触核蛋白异常被认为是导致PD和其他相关疾病中细胞死亡的事件。 疾病因此，了解α-突触核蛋白异常如何导致脑中神经元死亡将有助于 提供更好的了解PD，并可能导致治疗方法，将针对 导致PD的潜在过程。