ER Stress-induced Neurodegeneration as Therapeutic Targets for ALS

 描述（由申请人提供）： 肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，影响退伍军人和普通人群。目前尚无有效的治疗方法，大多数患者在发病后2年内死亡。ALS的一个重要神经病理学标志是受影响神经元内错误折叠蛋白的积累，其渐进地且不可逆地激活内质网（ER）应激细胞死亡机制。事实上，越来越多的证据表明，ER应激是ALS中驱动神经毒性的重要机制。然而，目前尚不清楚ER应激如何导致ALS中的细胞凋亡，或者这种高度保守的机制是否可以用于开发治疗靶点，这些靶点可以提高神经元重置未折叠蛋白反应（UPR）稳态的能力，减轻疾病进展，并延长ALS患者的生存期。这项新的RR&D Merit Review提案将开发小分子化学物质，在ALS的临床前模型中阻断ER应激诱导的神经变性。我们未发表的数据支持应激激活蛋白激酶HIPK 2（同源域相互作用蛋白激酶2）在激活化学试剂诱导的ER应激和突变SOD 1G93 A蛋白引起的神经退行性变小鼠模型中发挥重要作用。有趣的是，在家族性和散发性ALS患者的组织中也发现了类似的HIPK2激活。总之，这些结果提供了原理性证据，即阻断HIPK2可以保护家族性和散发性ALS中由错误折叠突变蛋白引起的运动神经元神经变性。如果成功，我们的研究将对ALS患者的诊断，治疗和康复产生深远的影响。

 DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects the Veterans and the general population. Currently, there is no effective treatment and most patients die within 2 years after disease onset. One important neuropathology hallmark of ALS is the accumulation of misfolded proteins within the affected neurons, which progressively and irreversibly activate endoplasmic reticulum (ER) stress cell death mechanisms. Indeed, there is mounting evidence that ER stress is an important mechanism driving neurotoxicity in ALS. However, it is unclear how ER stress leads to apoptosis in ALS or whether this highly conserved mechanism can be harnessed to develop therapeutic targets that can improve the ability of neurons to reset the homeostasis of unfolded protein response (UPR), mitigate the disease progression, and prolong the survival in ALS patients. This new RR&D Merit Review proposal will develop small molecule chemicals that block ER stress-induced neurodegeneration in pre-clinical models of ALS. Our unpublished data support an important role of stress-activated protein kinase HIPK2 (homeodomain interacting protein kinase 2) in activating ER stress induced by chemical agents and in mouse model of neurodegeneration caused by mutant SOD1G93A protein. Interestingly, similar HIPK2 activation has also been identified in tissues from patients with familial and sporadic ALS. Together, these results provide proof-of-principle evidence that blocking HIPK2 can protect motor neurons neurodegeneration caused by misfolded mutant proteins in familial and sporadic ALS. If successful, our research will have profound impacts on the diagnosis, treatment, and rehabilitation of Veterans who suffer from ALS.