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: 8803815
• 负责人: Matthew S Goldberg
• 金额: $ 18.38万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803815
• 关键词: Affect; Age; Alanine; Animal Model; Aspartic Acid; Astrocytes; Beds; Behavior; Behavioral; Brain; Cell Culture Techniques; Cell Death; Cells; Clinical; Complement; Corpus striatum structure; Cultured Cells; Custom; Cysteine; Cytoprotection; DNA Sequence Alteration; Data; Development; Disease; Disease Progression; Disease model; Dopamine; Drosophila genus; Elderly; Event; Exhibits; Genes; Genetic; Health; Human; Immunohistochemistry; In Vitro; Inherited; Intervention; Knock-out; Knockout Mice; Laboratories; Lentivirus Vector; Lewy Bodies; Life; Link; Mediating; Mission; Modeling; Modification; Molecular; Movement Disorders; Mus; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Outcome Measure; Oxidative Stress; PINK1 gene; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Physiological; Premature Mortality; Proteins; Publishing; Rattus; Risk Factors; Rodent Model; Serine; Severities; Substantia nigra structure; Symptoms; Testing; Therapeutic; Time; Tissues; United States National Institutes of Health; Variant; age related; astrocyte mediated neuroprotection; base; behavioral impairment; brain cell; brain tissue; disability; disorder risk; dopaminergic neuron; effective therapy; experience; in vivo; innovation; loss of function mutation; motor disorder; neurochemistry; neuron loss; novel; oxidation; palliative; parkin gene/protein; prevent; sensor; synuclein; therapeutic development; viral gene delivery

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 based on previous in vitro studies of DJ-1 function and pathogenic mechanisms of DJ-1 mutations: 1) To determine whether DJ-1 expression in neurons, astrocytes or both is required to prevent age-dependent loss of nigral dopamine neurons in rats and 2) To determine whether DJ-1 cysteine 106 is required for DJ-1 in vivo to prevent nigral cell loss. 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 cysteine 106 is required for DJ-1 to prevent nigral cell loss in DJ-1 KO rats and the second main hypothesis that DJ-1 expression in astrocytes is required 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 by 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）是老年人神经变性、残疾和过早死亡的常见原因。黑质多巴胺能神经元的缺失是PD的主要神经病理学标志。目前还没有治疗方法证明可以减缓PD中进行性黑质细胞丢失，这会导致临床症状的严重程度增加。最近人类基因突变如Parkin、DJ-1和PINK 1与复发性遗传形式的PD之间的联系为发现致病机制以及基于与人类帕金森症生理学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。我们已经使用基因敲除（KO）小鼠追求这一策略十多年了。由于未知的原因，在没有进一步损伤的情况下，Parkin KO、DJ-1 KO和PINK 1 KO小鼠不会再现在这些基因中携带功能丧失突变的人类中发生的黑质细胞损失。黑质细胞损失的缺乏排除了使用黑质细胞损失作为直接测试Parkin KO、DJ-1 KO或PINK 1 KO小鼠中的潜在致病机制和神经保护策略的结果量度。最近开发的DJ-1 KO大鼠表现出年龄依赖性黑质细胞损失，在4个月和6个月时多巴胺神经元完全补充，但在8个月时损失超过50%。DJ-1 KO大鼠中的年龄依赖性黑质神经元损失使得有可能首次在再现PD的中枢神经病理学特征的哺乳动物大脑中直接测试候选致病机制。基于先前对DJ-1功能和DJ-1突变致病机制的体外研究，我们建议使用DJ-1 KO大鼠实现以下特定目标：1）为了确定DJ-1在神经元中的表达，星形胶质细胞或两者都是防止大鼠中黑质多巴胺神经元的年龄依赖性损失所必需的，以及2）为了确定DJ-1半胱氨酸106是否是DJ-1-多巴胺神经元的年龄依赖性损失所必需的，1，以防止黑质细胞损失。我们期望通过检验DJ-1 KO大鼠中半胱氨酸106是DJ-1防止黑质细胞损失所需的主要假设和第二个主要假设，即星形胶质细胞中DJ-1表达是DJ-1 KO大鼠防止黑质细胞损失所需的，来对DJ-1 KO大鼠进行系统表征，作为治疗开发的适当试验床。使用这种新的黑质细胞丢失大鼠模型是创新的，该提案将通过将重点转移到PD脑组织中存在的疾病机制来显著影响对PD的理解，这些疾病机制因其强大的治疗潜力而被选择。我们希望我们的研究结果将广泛适用于家族性和散发性PD以及其他神经退行性疾病的神经保护疗法的开发。

项目成果

New Developments in Genetic rat models of Parkinson's Disease.

• DOI: 10.1002/mds.27296
• 发表时间: 2018-05
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Creed RB;Goldberg MS
• 通讯作者: Goldberg MS