DJ1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson s Disease

帕金森病（PD）是一种常见的与年龄相关的慢性神经退行性疾病，以运动为主，但也有一些非运动疾病的表现，严重损害患者的生活质量，并造成沉重的社会经济负担。目前的治疗是对症的，可以控制大多数运动症状，但没有治愈或改善疾病的疗法。因此，有必要更多地了解pd相关的神经退行性变途径，以确定新的治疗机会。在过去十年中，通过确定导致家族性疾病的遗传因素，在开始揭示这种途径方面取得了重大进展。其中一个遗传因素就是DJ-1。DJ-1的功能丧失突变与罕见的隐性家族性帕金森病有关。在体内，DJ-1的缺失加重了MPTP或缺血性脑损伤后的神经元功能障碍和死亡，其给药或替代具有神经保护作用。为了研究这些通路，我们建议使用PD的遗传小鼠模型，专门模拟神经元功能障碍，并将它们交叉到DJ-1缺陷小鼠身上。这两种具有PD相关表型的小鼠分别表达异常的致病形式的α -突触核蛋白和LRRK2，但它们的表型是轻微的，让人联想到早期或症状前的PD。通过在这两个模型中去除DJ-1，我们期望释放神经变性，从而诱导更接近全身性帕金森病的表型。我们将通过一组组学/系统方法，从行为学、神经病理学和表征神经退行性变途径的角度分析新模型。为了描述疾病进展，我们将在不同年龄组中进行这些分析：在疾病发病前和疾病表现高峰期。我们将对数据进行统计评估和网络重建，以确定疾病发生和进展的潜在新关键参与者。

Parkinson s disease (PD) is a common, age-related chronic neurodegenerative disorder with major motor, but also a number of non-motor disease manifestations that significantly impair the quality of life of afflicted patients and impose a heavy socio-economic burden. Current treatments are symptomatic and can manage most motor symptoms, but there is no cure or disease-modifying therapy. It is therefore essential to gain more insight into PD-relevant neurodegeneration pathways in order to define novel therapeutic opportunities. Major advances have been achieved over the last decade in starting to uncover such pathways by the identification of genetic factors responsible for familial forms of the disease. One such genetic factor is DJ-1. Loss-of-function mutations of DJ-1 are associated with rare recessive forms of familial PD. In vivo, deletion of DJ-1 exacerbates neuronal dysfunction and death in response to MPTP or ischemic brain injury, and its administration or replacement is neuroprotective. To study these pathways, we propose to use genetic mouse models of PD that model specifically neuronal dysfunction and cross them onto DJ-1 deficient mice. The two mouse lines with a PD-relevant phenotype express abnormal, pathogenic forms of alpha-synuclein and LRRK2, respectively, but their phenotype is mild and reminiscent of early or pre-symptomatic PD. Through the removal of DJ-1 in these two models, we expect to unleash neurodegeneration that will induce a phenotype closer to full-blown PD. We will analyze the new models behaviourally, neuropathologically, and, to characterize the neurodegeneration pathways, by a set of omics/systems approaches. To characterize disease progression, we will do these analyses in different age groups: before disease onset, and at peak disease manifestation. We will subject the data to statistical evaluation and network reconstruction to identify potential new key players of disease initiation and progression.