MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS.
Proc Natl Acad Sci U S A
; 110(29): 12066-71, 2013 Jul 16.
Article
em En
| MEDLINE
| ID: mdl-23818595
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Superóxido Dismutase
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Proteínas Serina-Treonina Quinases
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Ativação Enzimática
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Esclerose Lateral Amiotrófica
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Neurônios Motores
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2013
Tipo de documento:
Article