Mechanisms of Mixed Tau and a-Synuclein Pathogenesis

描述(由申请人提供)：痴呆症是一种常见的、使人虚弱的特征，在40%-70%的帕金森病(PD)患者中发生，PD患者的发病率大约是年龄匹配的对照组的6倍。一些独立的神经病理学家指出，大约50%的帕金森病痴呆(PDD)患者的脑部改变符合阿尔茨海默病(AD)和帕金森病(PD)的病理诊断标准。这些发现表明，混合病理是令人惊讶的常见，共同的通路可能导致tau和1-突触核蛋白的异常沉积。然而，混合病理发展的潜在机制是谜，目前还没有明确的模型来评估它们。一些令人兴奋的新观察表明，我们的DJ-1缺陷小鼠系(即DJ-1缺失外显子7(DJ-1-/-))可能首次提供了一种解决这些机制的模型。我们现在有了在老年DJ-1-/-小鼠身上的初步数据，显示出强大的磷酸化tau和？-突触核蛋白在整个大脑中积聚，这可能代表了早期神经退行性混合病理。我们的初步分析表明，这些变化伴随着1)黑质神经细胞的丢失，2)氧化损伤的证据，3)伴侣蛋白的耗竭，这表明DJ-1功能的缺失可能导致神经变性和β-突触核蛋白和tau包涵体的发展。因此，DJ-1-/-小鼠可以作为一种新的和重要的工具来研究帕金森病和痴呆症疾病中导致细胞死亡和混合病理的途径。这项建议的目的是利用我们的空DJ-1模型，并首次探索？-突触核蛋白、tau和DJ-1之间的关系，以及这些相互作用在混合tau和？-突触核病的病理生理学中的潜在作用。公共卫生相关性：这项研究的长期目标是阐明治疗或预防帕金森氏病(PD)认知功能下降的新目标，帕金森病是导致该疾病残疾的主要和不可治疗的原因，重要的起点是更好地了解PD痴呆的病理基础和促进疾病发展的潜在机制。我们的神经病理学证据表明，我们第一次有了一个啮齿动物模型来评估这些途径，并对导致变性和混合突触核蛋白和tau病理的蛋白质-蛋白质相互作用获得了新的见解。本申请中提出的研究将有助于确定导致tau和？-突触核蛋白致病的确切机制(例如，DJ-1缺乏和/或毒物暴露造成的氧化应激)，这些蛋白与DJ-1的关系，以及基因-环境和基因-基因相互作用在导致帕金森痴呆的病理生理学中的影响。

DESCRIPTION (provided by applicant): Dementia is a common, debilitating feature that develops in 40-70% of patients with Parkinson's disease (PD) with an incidence approximately six times higher in PD patients than age-matched controls. Several independent neuropathologists have indicated that approximately 50% of patients with PD-dementia (PDD) will have changes in brain that meet pathological criteria for a diagnosis of both Alzheimer's disease (AD) and PD. Such findings indicate that mixed pathology is surprisingly common and that shared pathways likely contribute to abnormal deposition of tau and 1-synuclein. The mechanisms underlying the development of mixed pathology, however, are enigmatic, and no clear-cut model for their evaluation currently exists. Several exciting new observations indicate that our line of DJ-1-deficient mouse (i.e. DJ-1 deletion Exon 7 (DJ-1-/-)) may provide, for the first time, a model to address these mechanisms. We now have preliminary data in aged DJ-1-/- mice demonstrating robust phosphorylated tau and ?-synuclein accumulation throughout the brain, in what may represent early neurodegenerative mixed pathology. Our initial analyses show that these changes are accompanied by i) neuronal cell loss in the substantia nigra, ii) evidence of oxidative damage and iii) chaperone depletion, suggesting that the absence of DJ-1 function could contribute to neurodegeneration and the development of ? -synuclein and tau inclusions. Thus, the DJ-1-/- mouse could be used as a novel and important tool to investigate pathways leading to cell death and mixed pathology in disorders with parkinsonism and dementia. The purpose of this proposal is to take advantage of our null DJ-1 model and to explore, for the first time, the relationship between ?-synuclein, tau and DJ-1, and the potential role of these interactions, in the pathophysiology underlying mixed tau and ?-synucleinopathies. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to elucidate novel targets for treating or preventing cognitive decline in Parkinson's disease (PD), a major and untreatable cause of disability in the disorder, and an essential starting point is to better understand the pathological substrates of dementia in PD and the underlying mechanisms that contribute to disease development. Our neuropathological evidence suggests, that for the first time, we have a rodent model to evaluate these pathways and gain novel insight into the protein-protein interactions that lead to degeneration and mixed ? -synuclein and tau pathology. The studies proposed in this application should be useful in determining precise mechanisms that contribute to tau and ?-synuclein pathogenesis (e.g., oxidative stress from DJ-1 deficiency and/or toxicant exposure), the relationship of these proteins with DJ-1 and the impact of gene-environment and gene-gene interactions in pathophysiology leading to parkinsonism with dementia.