Neuroprotective Activity of DJ-1 in Parkinson's Disease

描述(申请人提供)：在过去的十年中，几种遗传形式的帕金森病(PD)的基因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侮辱的反应以及它们在这种疾病中的死亡的机制研究成为可能。DJ-1是到目前为止发现的与遗传性帕金森病有关的五个基因之一。在患病家系中发现的DJ-1基因座位上的两个原始突变的隐性传递表明，正常的DJ-1在多巴胺能神经元中起神经保护分子的作用，这种特性随着疾病导致突变而丢失。这项申请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帕金森病。第一个具体目的是扩大我们最近的发现，即野生型DJ-1抑制Daxx/ASK1死亡信号通路，利用细胞模型研究DJ-1的各种突变如何影响这一凋亡机制，以及DJ-1的抗氧化功能如何与这一途径相关。第二个具体目标将解决这一途径在帕金森病受试者和基因工程小鼠大脑中的体内相关性。第三个特定目标是DJ-1通过Daxx依赖和Daxx非依赖机制调节对多巴胺能神经元存活至关重要的基因的转录，从而发挥细胞保护功能。这些研究的最终目标是通过确定治疗干预的潜在靶点来减轻帕金森氏症的负担，这些治疗干预也可以使散发性帕金森病受益。普通大众：DJ-1基因突变是遗传性帕金森氏症的原因之一。该项目的目标是了解DJ-1的正常功能，以及这些功能的缺陷如何导致大脑中的神经细胞退化。澄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.