Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease.
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.
Landau
Anne M
AM
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Luk
Kelvin C
KC
Jones
Michelle-Lee
ML
Siegrist-Johnstone
Rosmarie
R
Young
Yoon Kow
YK
Kouassi
Edouard
E
Rymar
Vladimir V
VV
Dagher
Alain
A
Sadikot
Abbas F
AF
Desbarats
Julie
J
D000368:Aged; D000818:Animals; D001921:Brain / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008232:Lymphoproliferative Disorders / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D019014:fas Receptor