Cathepsin D as a therapeutic tool for Parkinson's disease

描述（由申请人提供）：本申请是根据PAR-08-232提交的。帕金森病（PD）是一种无法治愈的进行性神经退行性疾病，其特征在于与黑质中多巴胺能神经元的损失相关的运动功能障碍。虽然在疾病的初始阶段可以成功地控制症状，但仍然缺乏针对PD病理的有效长期治疗。在病理学上，散发性和家族性PD病例的特征还在于存在称为路易体和路易神经突的脑内含物，其主要由纤维状1-突触核蛋白（1- syn）组成。1-syn在PD发病机制中的中心作用进一步得到了常染色体显性PD病例亚组中1-syn基因点突变和遗传倍增的发现的支持。这些基因突变和倍增导致聚集的1-syn种类增加，这被认为与神经元毒性有关。因此，增加单体1-syn（以防止聚集）和/或聚集的1-syn种类（以阻止或逆转聚集）的清除的策略应防止或减少PD病理。我们发表的数据表明，在溶酶体中，1-syn主要由组织蛋白酶D（Cat. D）降解，并且1-syn水平可以通过Cat. D活性的变化来操纵。在本申请中，我们将测试Cat. D在PD动物模型中预防或减少1-syn病理的潜力。我们将使用两种充分表征的表达WT和A53 T突变体人1-syn的小鼠模型，除了脑内含物外，还显示出运动缺陷。将使用重组腺相关病毒（rAAV）技术将D类药物递送至新生和成年动物的大脑，并通过生物化学和免疫组织化学方法测量病理学和疾病进展。我们的研究将提供关于Cat. D作为PD治疗工具的可行性的信息。 公共卫生相关性：帕金森氏病（PD）是最常见的运动障碍，在美国影响超过50万人，每年诊断出约5万例新病例。PD是无法治愈的，目前的治疗大多集中在疾病症状上。在本申请中，我们建议通过靶向1-突触核蛋白（一种参与PD病理学的蛋白质）来研究该疾病的新预防和治疗策略。

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.