Cell Senescence and Death in Neurodegenerative Diseases

项目概要/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患者均 硬化症（ALS）患者失去肌肉质量作为细胞（运动神经元; MN），连接到肌肉在四肢控制 运动停止工作，最终死亡。然而，神经系统结构和功能的复杂性， 系统是通过广泛的发展过程实现的，并在一定程度上由于系统的弹性而得以维持。 细胞维持功能和抵抗激活细胞死亡过程。因此，似乎存在广泛的 在最初的神经元功能障碍和身体退化之间的延迟。本提案中的实验将研究 新的假说：ALS中的运动神经元在神经肌肉（NMJ）去神经支配后进入细胞衰老， 一个复杂的应激反应，以避免积极的退化和细胞死亡。尽管这种保护性 这种机制可以保持细胞的物理存在，衰老细胞功能障碍和潜在的毒性。 分泌蛋白组随时间推移促进慢性组织变性，从而促进疾病进展。我们将进一步 研究良好表征衰老抑制剂的药理学给药是否可以有效地清除衰老 运动神经元和减少的神经毒性在ALS的SOD 1小鼠模型。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 大多数ALS患者在诊断后平均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.