Cathepsin D as a therapeutic tool for Parkinson's disease

组织蛋白酶 D 作为帕金森病的治疗工具

• 批准号: 8044937
• 负责人: DANIEL SEVLEVER
• 金额: $ 23.25万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044937
• 关键词: Affect; Animal Model; Biochemical; Birth; Brain; Brain Pathology; Brain region; Caenorhabditis elegans; Cathepsins; Cessation of life; Chronic; Clinical; Data; Deposition; Disease; Disease Progression; Dopamine; Drug resistance; Enzymes; Experimental Genetics; Functional disorder; Gene Delivery; Gene Mutation; Genes; Genetic; Goals; Grant; Human; Lead; Levodopa; Lewy Bodies; Link; Lysosomes; Measures; Methods; Modeling; Modification; Monitor; Motor; Movement Disorders; Mus; Mutation; Neurites; Neurodegenerative Disorders; Neurons; Newborn Animals; Operative Surgical Procedures; Outcome; Paper; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phosphorylation; Play; Point Mutation; Prevention; Preventive; Process; Proteins; Protocols documentation; Publishing; Quality of life; Recombinant adeno-associated virus (rAAV); Role; Staging; Substantia nigra structure; Survival Rate; Symptoms; Technology; Testing; Therapeutic; Toxic effect; Transgenic Animals; Transgenic Mice; Ubiquitination; Up-Regulation; Virus; adeno-associated viral vector; alpha synuclein; astrogliosis; base; disease diagnosis; dopaminergic neuron; enzyme activity; gene therapy; improved; locomotor deficit; mature animal; mouse model; mutant; neuroprotection; neurorestoration; neurotoxicity; neurotransmission; novel; overexpression; pars compacta; pre-clinical; premature; prevent; response; synuclein; tool; young adult

DESCRIPTION (provided by applicant): This application is submitted in response to PAR-08-232. Parkinson's disease (PD) is an incurable progressive neurodegenerative disorder characterized by motor dysfunctions associated with the loss of dopaminergic neurons in the substantia nigra pars compacta. Although, symptoms can be successfully controlled in the initial stages of the disease, effective long term therapies targeting PD pathology are still lacking. Pathologically, sporadic and familial PD cases are also characterized by the presence of brain inclusions known as Lewy bodies and Lewy neurites that are primarily composed of fibrillar 1-synuclein (1- syn). The central role of 1-syn in PD pathogenesis is further supported by the finding of point mutations and genetic multiplications in the 1-syn gene in a subset of autosomal-dominant PD cases. These genetic mutations and multiplications lead to an increase in aggregated 1-syn species, which are believed to be implicated in neuronal toxicity. Therefore, strategies to increase the clearance of monomeric 1-syn (to prevent aggregation) and/or of aggregated 1-syn species (to stop or reverse aggregation) should prevent or reduce PD pathology. Our published data show that, in lysosomes, 1-syn is primarily degraded by cathepsin D (Cat. D), and that 1-syn levels can be manipulated by changes in Cat. D activity. In this application, we will test the potential of Cat. D to prevent or reduce 1-syn pathology in animal models of PD. We will use two well characterized mouse models expressing WT and A53T mutant human 1-syn, that in addition to brain inclusions, show locomotor deficits. Cat. D will be delivered to the brains of newborn and adult animals, using recombinant adeno-associated virus (rAAV) technology, and the pathology and disease progression will be measured by biochemical and immunohistochemical methods. Our studies will provide information on the feasibility of Cat. D as a therapeutic tool for PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the most common movement disorder affecting more than 500,000 people in the US, and about 50,000 new cases of the disease are diagnosed every year. PD is incurable and current treatments are for most part focused on the disease symptoms. In this application, we propose to investigate new preventive and therapeutic strategies for the disease by targeting 1-synuclein, a protein involved in PD pathology.

描述(申请人提供)：本申请是根据PAR-08-232的要求提交的。帕金森病(PD)是一种不可治愈的进行性神经退行性疾病，其特征是运动功能障碍与黑质致密部多巴胺能神经元的丢失有关。虽然在疾病的初期症状可以成功控制，但针对帕金森病病理的有效长期治疗仍然缺乏。病理上，散发性和家族性帕金森病的特点还包括脑内包涵体的存在，这些包涵体主要由纤维状1-突触核蛋白(1-syn)组成，称为路易小体和路易氏突起。在一组常染色体显性遗传性帕金森病患者中发现了1-syn基因点突变和遗传倍增，进一步支持了1-syn在PD发病机制中的中心作用。这些基因突变和倍增导致聚集的1-SYN物种增加，这被认为与神经元毒性有关。因此，增加单体1-syn的清除(防止聚集)和/或聚集的1-syn物种的清除(停止或逆转聚集)的策略应该可以预防或减少PD的病理。我们已发表的数据表明，在溶酶体中，1-syn主要被组织蛋白酶D(Cat.D)，并且1-syn水平可以通过Cat中的变化来操纵。D活动。在本应用程序中，我们将测试Cat的潜力。预防或减少帕金森病动物模型的1-SYN病理改变。我们将使用两个具有良好特征的小鼠模型来表达WT和A53T突变的人1-syn，除了大脑包涵体外，还显示出运动障碍。猫。利用重组腺相关病毒(RAAV)技术，D将被输送到新生和成年动物的大脑中，并将通过生化和免疫组织化学方法测量病理和疾病进展。我们的研究将为Cat的可行性提供信息。D作为帕金森病的治疗工具。 公共卫生意义：帕金森氏症(PD)是美国最常见的运动障碍，影响着50多万人，每年约有5万新确诊病例。帕金森病是不治之症，目前的治疗大多集中在疾病症状上。在这项应用中，我们建议通过靶向1-突触核蛋白来研究疾病的新预防和治疗策略，1-突触核蛋白是参与帕金森病病理的一种蛋白质。