Neuroprotective Activity of DJ-1 in Parkinson's Disease

描述（由申请人提供）：在过去的十年中，几种遗传形式的帕金森病（PD）的遗传特征使得对多巴胺能神经元存活的分子决定因素、这些神经元对内源性和外源性损伤的反应以及它们在这种疾病中的死亡的机制研究得以进行。DJ-1是迄今已确定的与遗传性帕金森病有关的五个基因之一。在患病家系的DJ-1基因座中发现的两个原始突变的隐性传播表明，正常的DJ-1在多巴胺能神经元中起神经保护分子的作用，而这种特性随着致病突变而丧失。本应用程序旨在阐明这些神经保护机制，并解决这些过程中的扰动如何导致PD。第一个具体目标是扩展我们最近发现的野生型DJ-1抑制Daxx/ASK1死亡信号通路，通过细胞模型研究DJ-1的各种突变如何影响这种凋亡机制，以及DJ-1的抗氧化功能如何与该途径相关。第二个具体目标将解决该途径在PD受试者和基因工程小鼠大脑中的体内相关性。第三个具体目标是通过daxx依赖性和daxx非依赖性机制，通过调节多巴胺能神经元存活的关键基因的转录来研究DJ-1的细胞保护功能。这些研究的最终目的是通过确定治疗干预的潜在目标来减轻帕金森病的负担，这些干预也可以使散发性帕金森病受益。对于公众：DJ-1基因的突变是遗传性帕金森病的原因之一。这个项目的目标是了解DJ-1的正常功能，以及这些功能的缺陷如何导致大脑神经细胞变性。弄清这些事件有助于开发可能减缓或阻止脑细胞死亡的治疗方法。

DESCRIPTION (provided by applicant): The genetic characterization of several inherited forms of Parkinson's disease (PD) in the past decade has allowed the conduct of mechanistic studies about the molecular determinants of dopaminergic neuronal survival, the response of these neurons to endogenous and exogenous insults, and their demise in this disease. DJ-1 is one of five genes identified thus far to be linked to inherited PD. The recessive transmission of the two original mutations identified in the DJ-1 locus in affected pedigrees suggests that normal DJ-1 functions as a neuroprotective molecule in dopaminergic neurons, and that this property is lost with the disease causing mutations. This application proposes to elucidate these neuroprotective mechanisms and to address how perturbations in these processes lead to PD. The first specific aim proposes to expand on our recent discovery that wild-type DJ-1 inhibits the Daxx/ASK1 death signaling pathway, to investigate how various mutations in DJ-1 influence this apoptotic mechanism, and how the anti-oxidant function of DJ-1 relates to this pathway using cellular models. The second specific aim will address the in vivo relevance of this pathway in the brains of PD subjects and of genetically engineered mice. And the third specific aim focuses on the cytoprotective function of DJ-1 by modulating transcription of genes that are key to the survival of dopaminergic neurons both through Daxx-dependent and Daxx-independent mechanisms. The ultimate objective of these studies is to ease the Parkinson's disease burden by identifying potential targets for therapeutic interventions that can also benefit sporadic PD. For Lay public: Mutations in the DJ-1 gene is one of the causes of inherited Parkinson's disease. The goal of this project is to understand the normal functions of DJ-1 and how defects in these functions lead to nerve cell degeneration in the brain. Clarifying these events can help develop treatments that could potentially slow down or block brain cell death.