Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS

• DOI: 10.1038/s41419-018-0624-8
• Publication Date: 2018-05-22T12:22:49Z
• Authors: Katherine L. Gibbs; Bernadett Kalmar; Elena R. Rhymes; Alexander D. Fellows; Mahmood Ahmed; Paul Whiting; Ceri H. Davies; Linda Greensmith; Giampietro Schiavo
• Keywords: Axoplasmic transport

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically SOD1G93A mouse model ALS, proposed to play role neuron as well other pathologies nervous system, such Alzheimer's hereditary neuropathies. In this study, we screen library small-molecule kinase inhibitors towards identification pharmacological enhancers retrograde signalling endosomes, which might be used normalise rate process diseased Inhibitors p38 mitogen-activated protein kinases (p38 MAPK) were identified found correct deficits endosomes cultured primary vitro knockdown experiments revealed that alpha isoform MAPK MAPKα) was sole responsible for SOD1G93A-induced deficits. Furthermore, acute treatment with MAPKα restored physiological vivo early symptomatic mice. Our findings demonstrate pathogenic effect on identify potential therapeutic strategy ALS.