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 Our unpublished data support an important role of stress-activated protein kinase HIPK2 (homeodomain interacting protein kinase 2) in activating ER stress induced by chemical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.
Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by the selective degeneration of motor neurons in the central nervous system. Veterans with ALS suffer from severe muscle wasting/weakness and eventually die from respiratory failure. One consistent neuropathological feature in ALS is the presence of misfolded proteins in the spinal motor neurons, which activates irreversible cell death mechanism leading to neurodegeneration. In this application, we propose an array of interdisciplinary approaches to investigate if blocking the HIPK2 signaling pathway using pharmacological and genetic technologies will mitigate cell death in the several preclinical models of ALS. Results from this project will provide new insights into the ER stress- dependent cell death of spinal motor neurons, and new therapeutic targets to treating Veterans with ALS.
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