Mechanisms of Neurodegeneration in alpha-Synuclein Transgenic Mice

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。

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.