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

Jae Keun Lee, Jin Hee Shin, Sang Gil Hwang, Byoung Joo Gwag, Ann C. McKee, Junghee Lee, Neil W. Kowall, Hoon Ryu, Dae Sik Lim, Eui Ju Choi

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)12066-12071
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number29
DOIs
Publication statusPublished - 2013 Jul 16

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Amyotrophic Lateral Sclerosis
Motor Neurons
Spinal Cord
Thioredoxins
Autophagy
p38 Mitogen-Activated Protein Kinases
Caspases
Neurodegenerative Diseases
Oxidation-Reduction
Reactive Oxygen Species
Phosphotransferases
Superoxide Dismutase-1
Neurons
Mutation
Survival
Genes
Proteins

Keywords

  • Neurotoxicity
  • ROS

ASJC Scopus subject areas

  • General

Cite this

MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. / Lee, Jae Keun; Shin, Jin Hee; Hwang, Sang Gil; Gwag, Byoung Joo; McKee, Ann C.; Lee, Junghee; Kowall, Neil W.; Ryu, Hoon; Lim, Dae Sik; Choi, Eui Ju.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 29, 16.07.2013, p. 12066-12071.

Research output: Contribution to journalArticle

Lee, Jae Keun ; Shin, Jin Hee ; Hwang, Sang Gil ; Gwag, Byoung Joo ; McKee, Ann C. ; Lee, Junghee ; Kowall, Neil W. ; Ryu, Hoon ; Lim, Dae Sik ; Choi, Eui Ju. / MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 29. pp. 12066-12071.
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