Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu, Zn-superoxide dismutase (SOD1) causing the gain of its toxic property are the major culprit of familial ALS (fALS). The abnormal SOD1 aggregation in the motor neurons has been suggested as the major pathological hallmark of ALS patients. However, the development of pharmacological interventions against SOD1 still needs further investigation. In this study, using ELISA-based chemical screening with wild and mutant SOD1 proteins, we screened a new small molecule, PRG-A01, which could block the misfolding/aggregation of SOD1 or TDP-43. The drug rescued the cell death induced by mutant SOD1 in human neuroblastoma cell line. Administration of PRG-A01 into the ALS model mouse resulted in significant improvement of muscle strength, motor neuron viability and mobility with extended lifespan. These results suggest that SOD1 misfolding/aggregation is a potent therapeutic target for SOD1 related ALS.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons
All mutant types and WT-Superoxide dismutase 1 (SOD1) could induce the inclusions of GFP-WT-SOD1, which was distributed in cytosol (Fig. 1a and S1a)
WT-SOD1 aggregation could be induced by MTSOD1 through prion-like propagation, deregulation of TDP-43 and cellular stresses (Figs. 1, 3, S1, S3 and S4)
Summary
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons. Administration of PRG-A01 into the ALS model mouse resulted in significant improvement of muscle strength, motor neuron viability and mobility with extended lifespan These results suggest that SOD1 misfolding/aggregation is a potent therapeutic target for SOD1 related ALS. One of the important features of ALS is progressive disease[25,26], which means that neural cell death is propagated more over time through neural connection Concerning this feature, the prion-like propagation has been suggested for the progression of ALS; misfolded protein converts normal protein into abnormal protein[2,11,15,17,27]. The selected chemical, PRG-A01, worked as SOD1 inhibitor against misfolding/aggregation, which was able to inhibit the neuronal cell death caused by MT-SOD1 overexpression. We confirmed the therapeutic effect of PRG-A01 in vivo by addressing that it ameliorated motor neuron regression, movement disorder, and prolonged life span in SOD1G93A-Tg ALS mouse model
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