Mechanisms of Neurodegeneration in alpha-Synuclein Transgenic Mice

项目2：α-突触核蛋白转基因小鼠的神经退行性变机制。 虽然帕金森氏病(PD)的病因尚不清楚，但阿尔茨海默病的遗传和生化异常- 突触核蛋白直接参与帕金森病和其他阿尔法突触核病的发病机制。转基因(Tg) 表达A53T突变型人α-突触核蛋白的小鼠患上进行性成人起病 运动功能障碍会导致死亡。受影响的小鼠表现出许多人类阿尔法- 联体核病，包括a-Syn的异常聚集和皮质下区域的神经变性。 转基因小鼠阿尔法突触核病的特征揭示了氧化应激的迹象，包括线粒体 异常现象。因为线粒体异常和氧化应激都与 帕金森病的发病机制与其他a-突触核病，我们将探讨两者之间的病理关系 华星转基因小鼠的氧化应激和α-突触核变性。首先(目标1)，我们将确定 转基因小鼠的这种疾病与氧化应激有关，特别是与线粒体有关 异常现象。其次(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 异常会加剧α-突触核蛋白的病理和神经变性。最后，我们假设 氧化应激引起c-Abl的激活，c-Abl的激活直接参与疾病的发生。我们会 在小鼠和人类帕金森病病例中，α-突触核蛋白的病理与c-Abl的激活有关。我们 将表明缺乏c-Abl功能可以减轻α-突触核蛋白TG小鼠的神经退行性变。最后，我们 将显示c-Abl使α-突触核蛋白磷酸化，并且优先发现这种α-突触核蛋白 与聚集体相关联。此外，我们将与Project 1合作，确定阿尔法- 突触核蛋白病理导致Parkin功能缺陷并与Project 3确定突变体之间的连接 LRRK2和α-突触核蛋白在体内的病理学。这些研究将提供体内实验测试 与人类α-突触核病症的发病机制直接相关的过程，并可能导致 新的治疗方法。 相关性(请参阅说明)： α-突触核蛋白异常与帕金森病和其他相关疾病的细胞死亡有关 疾病。因此，了解α-突触核蛋白异常是如何导致脑内神经元死亡的 提供对帕金森病的更好的了解，并可能导致针对 负责PD的底层流程。

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.