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

项目摘要/摘要 帕金森病是第二种最常见的与年龄相关的神经退行性疾病。其根本原因是 特发性帕金森氏症尚不清楚。重要的是，已经发现了中脑的前驱炎症，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，并 发现人类帕金森氏症患者中脑中衰老细胞数量显著增加。 细胞衰老是一种根据DNA损伤信号激活的程序，可以防止有丝分裂细胞 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来招募免疫细胞和信号。 “过来吃我吧！”我们还发现，衰老的人类和小鼠的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。这项建议背后的理由是 细胞衰老是中脑的一种常见机制，导致多巴胺神经元丢失，从而导致 帕金森氏症。该提案的三个目标集中在1)解开与帕金森症相关的体外触发因素 对多巴胺能神经元细胞衰老的研究；2)衰老介导的激活的特征 免疫反应和衰老在中脑细胞类型之间的体外传播；3)体内 在中脑不同类型的细胞之间诱导和传播衰老。在建议的研究中，我们会 确定在多巴胺能神经元中诱导细胞衰老的途径，并确定对 衰老的扩散和免疫反应的激活。最后，我们将评估消融是否 在正确的时间点，中脑中的衰老细胞会干扰这种扩散，从而改善 中脑多巴胺能神经元的缺失。对衰老诱导的分子理解 随着对引发脑部炎症的重要释放因素的识别将有助于揭示一般情况 帕金森氏病和其他与年龄相关的神经退行性疾病的病理机制。此外，我们的发现 将对最终开发干预中脑衰老的方法具有直接的临床意义 延缓帕金森氏症的发展。

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.