Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease.
J Exp Med
; 202(5): 575-81, 2005 Sep 05.
Article
en En
| MEDLINE
| ID: mdl-16129703
ABSTRACT
Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Transducción de Señal
/
Regulación hacia Arriba
/
Receptor fas
/
Intoxicación por MPTP
/
Trastornos Linfoproliferativos
/
Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Aged
/
Animals
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Exp Med
Año:
2005
Tipo del documento:
Article
País de afiliación:
Canadá