MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS

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Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-Associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species-dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-Activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS.

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Lee, J. K., Shin, J. H., Hwang, S. G., Gwag, B. J., McKee, A. C., Lee, J., … Choi, E. J. (2013). MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 12066–12071. https://doi.org/10.1073/pnas.1300894110

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