Molecular Assessment of Cause and Consequence of Cellular Senescence in Diverse Midbrain Cell Types in Parkinson's Disease

项目总结/摘要 帕金森氏病是第二种最常见的与年龄相关的神经退行性疾病。的根本原因 原发性帕金森氏症是未知的。重要的是，中脑的前驱炎症已经被发现，但仍然存在 无法解释最近，我们发现多巴胺能神经元可以进入细胞衰老状态， 在帕金森病患者的中脑中发现了大量的衰老细胞。 细胞衰老是一个程序，在DNA损伤信号传导时被激活，并阻止有丝分裂细胞衰老。 不受控制的扩散。大多数衰老细胞表达所谓的衰老相关分泌表型。 这种表型的特征是分泌促炎因子，其募集免疫细胞并发出信号。 “过来吃了我！”。我们还发现，衰老的人类和小鼠多巴胺能神经元分泌 促炎因子并被激活的神经胶质细胞清除。这项建议的基本理由是， 细胞衰老是中脑中导致多巴胺神经元损失的一般机制， 帕金森氏症。该提案的三个目标集中在1）解开帕金森病相关的体外触发因素 多巴胺能神经元细胞衰老的特征; 2）衰老介导的多巴胺能神经元激活的特征。 免疫应答和衰老在中脑细胞类型之间的体外扩散;和3）体内衰老的细胞类型。 在中脑不同类型的细胞之间衰老的诱导和扩散。在拟议的研究中，我们将 确定多巴胺能神经元中诱导细胞衰老的途径，并确定对 衰老的蔓延和免疫反应的激活。最后，我们将评估是否消融 在适当的时间点，中脑中的衰老细胞将干扰扩散，从而可以改善 中脑多巴胺能神经元的丧失。对衰老诱导的分子理解 因为识别出对引发大脑炎症很重要的释放因子将有助于阐明 帕金森病和其他年龄相关的神经退行性疾病的病理机制。此外，我们的发现 将有直接的临床意义，最终开发出干扰中脑衰老的方法， 改善帕金森病的进展。

PROJECT SUMMARY/ABSTRACT Parkinson's disease is the second most common age-related neurodegenerative disorder. The underlying cause of idiopathic Parkinson's is unknown. Importantly, prodromal inflammation of the midbrain has been found but remains unexplained. Recently, we have discovered that dopaminergic neurons can enter a state of cellular senescence and found significantly elevated numbers of senescent cells in the midbrain of human Parkinson's disease patients. Cellular senescence is a program that gets activated upon DNA damage signaling and prevents mitotic cells from uncontrolled proliferation. Most senescent cells express the so-called senescence associated secretory phenotype. This phenotype is characterized by the secretion of proinflammatory factors that recruit immune cells and signal “come here and eat me!”. We have also found that senescent human and mouse dopaminergic neurons secrete pro-inflammatory factors and get removed by activated glial cells. The rationale underlying this proposal is that cellular senescence is a generic mechanism in the midbrain leading to dopamine neuron loss which results in Parkinson's disease. The three aims of the proposal focus on 1) unravelling the parkinsonism-related in vitro triggers of cellular senescence in dopaminergic neurons; 2) the characterization of senescence-mediated activation of immune responses and the in vitro spreading of senescence between cell types of the midbrain; and 3) the in vivo induction and spreading of senescence between diverse cell types in the midbrain. In the proposed study, we will identify pathways that induce cellular senescence in dopaminergic neurons and identify factors which are crucial for the spreading of senescence and the activation of an immune response. Finally, we will assess whether ablation of senescent cells in the midbrain at the right time point will interfere with the spreading and can thereby ameliorate the loss of dopaminergic neurons of the midbrain. The molecular understanding of the induction of senescence as well as the identification of released factors that are important to trigger brain inflammation will shed light on the general pathomechanism of Parkinson’s disease and other age-related neurodegenerative disorders. Moreover, our findings will have direct clinical implications to eventually develop methods to interfere with midbrain senescence to ameliorate the progression of Parkinson’s disease.