Role of MyD88-5 in the pathogenesis of Parkinson's disease

描述（由申请人提供）：帕金森病（PD）是一种神经退行性运动障碍，其特征是大脑中广泛的神经退行性变性，伴黑质致密部含多巴胺神经元的严重丧失。虽然大多数PD病例是散发的，但遗传突变约占PD病例的10%。现有证据表明应激激活蛋白激酶在帕金森病的发病机制中起着重要作用。神经元特异性c-jun n -末端激酶-3 （JNK3）的激活，随后向线粒体募集，与不可逆的神经变性有关。然而，这一过程背后的机制仍然知之甚少。我们克隆了一种神经元特异性线粒体蛋白MyD88-5，该蛋白富集于死后PD患者大脑的路易体和1-突触核蛋白诱导PD的小鼠模型中CNS的病理影响区域。我们发现MyD88-5的体外表达导致JNK3从细胞质募集到线粒体，并且MyD88-5敲除小鼠对帕金森神经毒素MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）引起的多巴胺能神经变性具有抗性。因此，我们假设MyD88-5可能将JNK3与线粒体依赖性细胞死亡联系起来。为了验证这一假设，提出了三个具体目标。目的1将使用MyD88-5敲除小鼠，研究MyD88-5在mptp诱导的PD中激活JNK3和介导多巴胺能细胞死亡中的作用。Aim 2将通过在MyD88-5基因敲除小鼠的黑质多巴胺能神经元中表达MyD88-5基因，或通过生成和测试a53t1 -synuclein转基因/MyD88-5缺失小鼠，来研究MyD88-5基因在突变型人a53t1 -synuclein诱导的PD发病机制中的作用。目的3将分析MyD88-5在MPTP和1-突触核蛋白诱导的PD中调节基底线粒体生理和功能的作用，这在PD的发展中都是重要的。总之，这些研究应该增加与PD神经退行性变相关的myd88 -5依赖性细胞损伤途径的知识，并有助于确定PD治疗的新治疗靶点。公共卫生相关性：本研究提出使用mptp -神经毒素和突变的人1-突触核蛋白小鼠模型来研究新发现的脑线粒体蛋白MyD88-5在帕金森病（PD）的发生和发展中的作用。该研究将丰富和完善我们对PD中myd88 -5依赖性细胞损伤通路的理解，并确定PD发病机制干预的新靶点。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by widespread neurodegeneration in the brain with profound loss of dopamine-containing neurons of the substantia nigra pars compacta. While majority of PD cases are sporadic, inherited mutations account for approximately 10% of PD cases. Existing evidence implicates a major role for stress activated protein kinases in the pathogenesis of PD. Activation of a neuronal specific c-jun N-terminal kinase-3 (JNK3), followed by recruitment to mitochondria, is associated with irreversible neurodegeneration. The mechanisms underlying this process however remain poorly understood. We have cloned a neuron-specific mitochondrial protein, called MyD88-5, which is enriched in Lewy bodies from brains of postmortem PD patients and in pathologically affected regions of the CNS in a mouse model of 1-synuclein induced PD. We showed that expression of MyD88-5 in vitro led to recruitment of JNK3 from the cytosol to mitochondria and that MyD88-5 knockout mice were resistant to dopaminergic neurodegeneration caused by parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We therefore hypothesize that MyD88-5 may link JNK3 to mitochondria-dependent cell death. Three specific aims are proposed to test this hypothesis. Aim 1 will examine the role of MyD88-5 in activating JNK3 and mediating dopaminergic cell death in MPTP-induced PD using MyD88-5 knockout mice. Aim 2 will examine the role of MyD88-5 in the pathogenesis of mutant human A53T 1-synuclein-induced PD by expressing this transgene in nigral dopaminergic neurons of MyD88-5 knockout mice, or by generating and testing A53T 1- synuclein transgenic/MyD88-5-null mice. Aim 3 will dissect the role of MyD88-5 in modulating basal mitochondrial physiology and function that are important in the PD development in both MPTP- and in 1-synuclein-induced PD using MyD88-5-null mouse. Together, these studies should increase knowledge of MyD88-5-dependent cell damage pathways associated with neurodegeneration in PD and help identify new therapeutic target(s) for the treatment of PD. PUBLIC HEALTH RELEVANCE: This study propose to examine the role of a newly discovered brain mitochondrial protein, MyD88-5, in the onset and development of Parkinson's disease (PD) using the MPTP-neurotoxin and mutant human 1-synuclein mouse models. The study will enrich and refine our understanding of MyD88-5-dependent cell damage pathways observed in PD and identify new target(s) for intervention in PD pathogenesis.