Mechanisms of Mixed Tau and a-Synuclein Pathogenesis

描述（由申请人提供）：痴呆是一种常见的使人衰弱的特征，在40-70%的帕金森病（PD）患者中发生，PD患者的发病率比年龄匹配的对照组高约6倍。几位独立的神经病理学家已经指出，大约50%的PD-痴呆（PDD）患者的大脑变化符合阿尔茨海默病（AD）和PD诊断的病理标准。这些发现表明，混合病理是令人惊讶的常见，共享的途径可能有助于异常沉积的tau和1-突触核蛋白。然而，混合病理发展的机制是神秘的，目前还没有明确的评估模型。几个令人兴奋的新观察结果表明，我们的DJ-1缺陷小鼠（即DJ-1缺失外显子7（DJ-1-/-））系可能首次提供了解决这些机制的模型。我们现在有了老年DJ-1-/-小鼠的初步数据，证明了强大的磷酸化tau蛋白和？突触核蛋白在整个脑中积聚，这可能代表早期神经退行性混合病理学。我们的初步分析表明，这些变化伴随着i）黑质神经元细胞损失，ii）氧化损伤的证据和iii）伴侣蛋白耗尽，这表明DJ-1功能的缺乏可能有助于神经变性和发展？- 突触核蛋白和tau内含物。因此，DJ-1-/-小鼠可用作一种新的和重要的工具，以研究导致细胞死亡和帕金森综合征和痴呆症的混合病理学的途径。本提案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，以及这些相互作用的潜在作用，在病理生理学基础的混合tau和？共核蛋白病公共卫生相关性：这项研究的长期目标是阐明治疗或预防帕金森病（PD）认知功能下降的新靶点，帕金森病是该疾病中残疾的主要和不可治疗的原因，一个重要的起点是更好地了解PD痴呆的病理学基础和导致疾病发展的潜在机制。我们的神经病理学证据表明，这是第一次，我们有一个啮齿动物模型来评估这些途径，并获得新的见解蛋白质-蛋白质相互作用，导致变性和混合？- 突触核蛋白和tau病理学。本申请中提出的研究应有助于确定有助于tau蛋白和？突触核蛋白发病机制（例如，来自DJ-1缺乏和/或毒物暴露的氧化应激）、这些蛋白质与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症与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.