A slowly progressive, endogenous synucleinopathy model of Parkinson's disease

项目摘要： 帕金森病（PD）的疾病改善疗法的开发和测试是有限的，部分原因是， 缺乏预测性的动物模型。我们建议开发和表征一个更好的，更具预测性的 模型，具有（i）更现实的时间过程，（ii）适当的病理和行为终点， (iii)在疾病过程中的临床相关点进行治疗干预的机会（例如， 出现症状后）。我们相信新模式将设置更高、更现实的障碍 对于实验性的，疾病修饰疗法，这样做，将有更多的预测价值， 临床发展。简而言之，用鱼藤酮处理野生型大鼠5天（而不是典型的 14-21天），在此期间，他们表现出轻微的帕金森病行为。停止使用鱼藤酮后， 大鼠恢复并且行为正常。在9 - 10周的潜伏期后，所有大鼠开始 表现出轻微的帕金森病症状，在随后的几周内持续恶化 数月。初步病理评估显示黑质多巴胺神经元进行性 在行为体征出现之前很久就积累了异常的内源性α-突触核蛋白， 与增加小胶质细胞激活有关。我们现在建议进一步描述这个模型， 测试治疗干预，目的如下：（1）表征选定的“临床”或 在一年的时间里，这个模型的行为方面。行为包括姿势不稳定 测试（PIT）、直立、翻正行为和步态。(2)为了表征该模型中随时间的病理学， 包括黑质纹状体细胞和终末丢失、α-突触核蛋白病理学和炎症标志物。（三） 测试症状发作后的治疗干预（α-突触核蛋白敲低）-一种情况 与临床医学非常相似，目前PD的诊断取决于是否存在以下因素： 症状

Project Summary: Development and testing of disease-modifying therapies for Parkinson's disease (PD) is limited, in part, by lack of predictive animal models. We propose to develop and characterize a better, more predictive model, with (i) a more realistic time course, (ii) appropriate pathological and behavioral endpoints and (iii) opportunities to intervene therapeutically at clinically relevant points in the disease course (e.g., after development of symptoms). We believe the new model will set a higher and more realistic hurdle for experimental, disease-modifying therapies, and in so doing, will have more predictive value for clinical development. In brief, wildtype rats are treated with rotenone for 5 days (instead of the typical 14-21 days), during which they displayed mild parkinsonian behavior. After cessation of the rotenone, the rats recover and are behaviorally normal. After a latency of 9 – 10 weeks, all of the rats begin to exhibit mild parkinsonian signs that have continued to worsen progressively over succeeding weeks and months. Preliminary pathological assessment reveals that nigral dopamine neurons progressively accumulate abnormal endogenous α-synuclein long before behavioral signs appear and this is associated with increasing microglial activation. We now propose to further characterize this model and to test a therapeutic intervention with the following aims: (1) To characterize selected `clinical' or behavioral aspects of this model over the course of 1 year. Behaviors include the Postural Instability Test (PIT), rearing, righting behavior and gait. (2) To characterize over time the pathology in this model, including nigrostriatal cell and terminal loss, α-synuclein pathology and markers of inflammation. (3) To test a therapeutic intervention (α-synuclein knockdown) after the onset of symptoms – a situation closely analogous to clinical medicine, where a diagnosis of PD currently depends on the presence of symptoms.