Mechanisms of protection against age-dependent nigral neuron loss in DJ-1 KO rats

DJ-1 KO 大鼠年龄依赖性黑质神经元丢失的保护机制

• 批准号: 8988758
• 负责人: Matthew S Goldberg
• 金额: $ 14.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8988758
• 关键词: Mechanisms; protection; against; age; dependent

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a frequent cause of neurodegeneration, disability and premature mortality in older adults. Loss of dopaminergic neurons in the substantia nigra is the primary neuropathological hallmark of PD. There are currently no treatments proven to slow down the progressive nigral cell loss in PD, which causes increasing severity of the clinical symptoms. The recent linking of human mutations in genes such as Parkin, DJ-1, and PINK1 to recessively inherited forms of PD provides new opportunities to discover pathogenic mechanisms and to develop and test neuroprotective therapies in animal models with nigral cell loss based on mechanisms physiologically relevant to human Parkinsonism. We have pursued this strategy for over a decade using knockout (KO) mice. For unknown reasons, without further insult, Parkin KO, DJ-1 KO and PINK1 KO mice do not reproduce the nigral cell loss that occurs in humans bearing loss-of-function mutations in these genes. The lack of nigral cell loss precludes using nigral cell loss as an outcome measure to directly test potential pathogenic mechanisms and neuroprotective strategies in Parkin KO, DJ-1 KO or PINK1 KO mice. Recently developed DJ-1 KO rats show age-dependent nigral cell loss with a full complement of dopamine neurons at ages 4 months and 6 months but greater than 50% loss by age 8 months. The age-dependent nigral neuron loss in DJ-1 KO rats makes it possible for the first time to test candidate pathogenic mechanisms directly in a mammalian brain that reproduces this central neuropathological feature of PD. We propose to use DJ-1 KO rats to achieve the following specific aims that we have chosen because of their significance for therapeutic development: 1) To define the cellular and molecular mechanisms by which DJ-1 is required to prevent age-dependent loss of nigral dopamine neurons in rats; 2) To determine whether inhibitors of the stress activated protein kinases c-jun-N-terminal kinase (JNK) or p38 prevent age-dependent loss of nigral dopamine neurons caused by DJ-1 deficiency. We expect to contribute a systematic characterization of DJ-1 KO rats as an apt test bed for therapeutic development by testing the principal hypothesis that DJ-1 deficiency causes increased signaling of stress-activated kinase pathways and the second main hypothesis that cysteine 106 is required for DJ-1 to prevent nigral cell loss in DJ-1 KO rats. The use of this novel rat model of nigral cell loss is innovative and the proposal will significantly impact the understanding of PD b shifting emphasis to disease mechanisms present in PD brain tissue selected for their strong therapeutic potential. We expect that our findings will be broadly applicable to the development of neuroprotective therapies for familial and sporadic PD as well as other neurodegenerative diseases.

描述（由申请人提供）：帕金森氏病（PD）是老年人神经退行性，残疾和过早死亡的经常原因。黑质中多巴胺能神经元的丧失是PD的主要神经病理学标志。目前尚无治疗方法可以减慢PD的进行性ni骨细胞损失，从而导致临床症状的严重程度增加。诸如Parkin，DJ-1和Pink1等基因中的人类突变与隐性遗传遗传的PD形式的最新联系为发现致病机制的新机会，并根据与人类帕金森氏症具有生理上有关的机制的动物模型中的动物模型中的动物模型中开发和测试神经保护疗法。我们已经使用淘汰（KO）小鼠追求了这一策略。出于未知原因，不进一步侮辱，帕金KO，DJ-1 KO和Pink1 KO小鼠不会再现这些基因功能丧失突变的人类中发生的ni骨细胞损失。缺乏使用ni骨细胞损失作为结果指标，无法直接测试Parkin KO，DJ-1 KO或Pink1 KO小鼠的潜在致病机制和神经保护策略的结果。最近开发的DJ-1 KO大鼠显示出年龄依赖性的ni骨细胞损失，在4个月零6个月的多巴胺神经元中完全补充，但到8个月大的损失大于50％。 DJ-1 KO大鼠中依赖年龄的ni元神经元丧失使得直接在哺乳动物大脑中直接测试候选病原机制，该机制再现了PD的这种主要神经病理学特征。我们建议使用DJ-1 KO大鼠实现我们选择的以下特定目标，因为它们对治疗性发育的重要性：1）定义了需要DJ-1的细胞和分子机制，以防止大鼠中依赖年龄依赖年龄依赖年龄的多巴胺神经元的年龄丧失； 2）确定应激激活蛋白激酶C-Jun-N-末端激酶（JNK）或p38是否可以防止DJ-1缺乏引起的ni核多巴胺神经元的年龄依赖性丧失。我们希望通过测试主要假设，即DJ-1缺乏症会导致压力激活激酶途径的信号增加，而第二个主要假设是CySteine 106需要DJ-1的dj-1来防止DJ-1 Ko rats dj-1 Ko rats dj-nigral损失，这是DJ-1 KO大鼠作为治疗开发的适当测试床的系统表征。这种新型大鼠ni骨细胞损失模型的使用是创新的，该提案将显着影响对PD B转移强调​​PD脑组织中存在的疾病机制的理解。我们预计我们的发现将广泛适用于针对家族和零星PD以及其他神经退行性疾病的神经保护疗法的发展。