Cell Senescence and Death in Neurodegenerative Diseases

项目摘要/摘要(30行) 无论家族史、发病部位、症状和进展顺序如何，所有肌萎缩侧索硬化症 硬化症(ALS)患者失去肌肉质量，因为连接到四肢肌肉的细胞(运动神经元；MNS)来控制 运动停止工作，最终消亡。然而，神经的结构和功能的复杂性 系统是通过广泛的开发过程实现的，并得到维护的部分原因是 维持细胞功能，抵抗激活细胞死亡过程。因此，出现了广泛的 最初的神经元功能障碍和身体退化之间的延迟。这项提案中的实验将调查一个 新假说：肌萎缩侧索硬化症中的运动神经元在神经肌肉(NMJ)失神经后进入细胞衰老 复杂的应激反应，以避免主动退化和细胞死亡。尽管如此，虽然这一保护性 机制可能是保存细胞的物理存在、衰老的细胞功能障碍和潜在的毒性 分泌体随着时间的推移促进慢性组织退化，从而促进疾病的进展。我们将进一步 研究具有良好特性的抗衰老药物的药理作用是否能有效地清除衰老 肌萎缩侧索硬化症SOD1小鼠模型的运动神经元和降低的神经毒性。这些实验的成功结果 将为ALS的研究开辟一条新的途径，并开发新的治疗靶点。一个迫切需要的地区 大多数ALS患者平均在确诊后2-4年死亡。

Project Summary/Abstract (30 lines) Regardless of family history, site of onset, and sequence of symptoms and progression, all Amyotrophic Lateral Sclerosis (ALS) patients lose muscle mass as the cells (motor neurons; MNs) that connect to muscle in limbs to control movement stop working and eventually die. However, the complexity of the structure and function of the nervous system is achieved through extensive developmental processes and is maintained in part due to the resiliency of the cells to maintain function and resist activating cell death processes. Therefore, there appears to be an extensive delay between initial neuronal dysfunction and physical degeneration. Experiments in this proposal will investigate a novel hypothesis: motoneurons in ALS enter cellular senescence following neuromuscular (NMJ) denervation as part of a complicated stress response to avoid active degeneration and cell death. Nonetheless, while this protective mechanism may preserve the physical presence of the cell, senescent cell dysfunction and potentially toxic secretome promotes chronic tissue degeneration over time that facilitates disease progression. We will further investigate if pharmacological administration of well-characterized senolytics can effectively clear senescent motoneurons and reduced neurotoxicity in the SOD1 mouse model of ALS. Successful outcome of these experiments will open a novel avenue of investigation in ALS and develop new therapeutic targets. An area desperately in need of development for the majority of ALS patients that die on average 2-4 years after diagnosis.