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）：帕金森病 (PD) 是老年人神经退行性变、残疾和过早死亡的常见原因。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。目前尚无任何治疗方法被证明可以减缓帕金森病中黑质细胞的进行性丧失，从而导致临床症状日益严重。最近，人类 Parkin、DJ-1 和 PINK1 等基因突变与隐性遗传的帕金森病形式之间存在联系，这为发现致病机制以及基于与人类帕金森病生理相关的机制在黑质细胞丧失的动物模型中开发和测试神经保护疗法提供了新的机会。十多年来，我们一直在使用基因敲除 (KO) 小鼠来推行这一策略。由于未知的原因，在没有进一步的损伤的情况下，Parkin KO、DJ-1 KO 和 PINK1 KO 小鼠不会重现在携带这些基因功能丧失突变的人类中发生的黑质细胞损失。由于缺乏黑质细胞损失，无法使用黑质细胞损失作为结果指标来直接测试 Parkin KO、DJ-1 KO 或 PINK1 KO 小鼠的潜在致病机制和神经保护策略。最近开发的 DJ-1 KO 大鼠在 4 个月和 6 个月大时表现出年龄依赖性黑质细胞损失，多巴胺神经元完全补充，但在 8 个月大时损失超过 50%。 DJ-1 KO 大鼠中年龄依赖性黑质神经元损失使得首次有可能直接在哺乳动物大脑中测试候选致病机制，从而再现 PD 的这种中枢神经病理学特征。我们建议使用 DJ-1 KO 大鼠来实现以下特定目标，我们选择这些目标是因为它们对治疗开发具有重要意义：1）确定 DJ-1 预防大鼠黑质多巴胺神经元年龄依赖性损失所需的细胞和分子机制； 2) 确定应激激活蛋白激酶 c-jun-N-末端激酶 (JNK) 或 p38 的抑制剂是否可以预防由 DJ-1 缺陷引起的黑质多巴胺神经元的年龄依赖性损失。我们希望通过测试主要假设（即 DJ-1 缺陷导致应激激活激酶途径信号传导增加）和第二个主要假设（DJ-1 需要半胱氨酸 106 来防止 DJ-1 KO 大鼠中黑质细胞损失），对 DJ-1 KO 大鼠作为治疗开发的合适试验台进行系统表征。这种新型黑质细胞丢失大鼠模型的使用具有创新性，该提案将显着影响对 PD 的理解，将重点转移到因具有强大治疗潜力而选择的 PD 脑组织中存在的疾病机制上。我们预计我们的研究结果将广泛适用于家族性和散发性帕金森病以及其他神经退行性疾病的神经保护疗法的开发。