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）：帕金森氏病（PD）是老年人神经退行性，残疾和过早死亡的经常原因。 Loss of dopaminergic neurons in the substantia nigra is the primary neuropathological hallmark of PD.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。 We have pursued this strategy for over a decade using knockout (KO) mice.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大鼠根据先前对DJ-1功能的体外研究和DJ-1突变的致病机制实现以下特定目标：1）确定是否需要DJ-1表达神经元，星形胶质细胞或两者兼而有之以防止年龄依赖于年龄依赖于大鼠的多巴胺神经元的年龄依赖性dj-1 cyste cyste cysteo cysteo是否依赖于DJ-1 cySte。 nigral cell loss.我们预计，通过测试主要假设，DJ-1需要DJ-1的主要假设来防止DJ-1 KO大鼠的nigral细胞损失，并且是第二个主要假设，即需要预防dj-1在DJ-1 JJ-ko中，DJ-1 KO大鼠是预防DJ-1的第二个主要假设，则可以预防DJ-1 KO大鼠的nigral细胞损失，以防止DJ-1表达DJ-1的第二个主要假设，以防止DJ-1 KO损失DJ-1 KO rats，DJ-1是可以预防DJ-1 KO大鼠的nigral损失，从而预防DJ-1的主要假说，DJ-1 KO大鼠是一种适当的治疗开发测试床的系统表征。这种新型大鼠ni骨细胞损失模型的使用是创新的，该提案将通过将重点转移到疾病机制中，从而对PD的理解产生重大影响，以供PD脑组织中存在的疾病机制，以表现其强大的治疗潜力。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。

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