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，其特征为大脑中广泛的神经退行性病变，伴有黑质背侧部含多巴胺神经元的严重缺失。虽然大多数PD病例是散发性的，但遗传性突变占PD病例的约10%。现有的证据表明，应激活化蛋白激酶在PD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（JNK 3）的激活，随后募集到线粒体，与不可逆的神经变性相关。然而，这一过程的机制仍然知之甚少。我们已经克隆了一个神经元特异性的线粒体蛋白，称为MyD 88 -5，这是丰富的路易体从死后PD患者的大脑和在1-突触核蛋白诱导的PD的小鼠模型中的CNS的病理受影响的地区。我们发现，MyD 88 -5在体外的表达导致JNK 3从胞质溶胶募集到线粒体，并且MyD 88 -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MyD 88 -5可能将JNK 3与细胞凋亡相关。提出了三个具体目标来检验这一假设。目的1：利用MyD 88 - 5基因敲除小鼠研究MyD 88 -5在MPTP诱导的PD中激活JNK 3和介导多巴胺能细胞死亡的作用。目的2将通过在MyD 88 -5敲除小鼠的黑质多巴胺能神经元中表达该转基因，或通过产生和测试A53 T1-突触核蛋白转基因/MyD 88 -5-null小鼠来检查MyD 88 -5在突变型人A53 T1-突触核蛋白诱导的PD的发病机制中的作用。目的3将使用MyD 88 -5缺失小鼠剖析MyD 88 -5在调节基础线粒体生理和功能中的作用，所述基础线粒体生理和功能在MPTP和1-突触核蛋白诱导的PD中的PD发展中是重要的。总之，这些研究应该增加与PD神经变性相关的MyD 88 -5依赖性细胞损伤途径的知识，并帮助确定治疗PD的新治疗靶点。公共卫生相关性：本研究拟采用MPTP神经毒素和突变型人1-突触核蛋白小鼠模型，研究新发现的脑线粒体蛋白MyD 88 -5在帕金森病（PD）发病和发展中的作用。该研究将丰富和完善我们对PD中观察到的MyD 88 -5依赖性细胞损伤途径的理解，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.