Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Annie Landau
  • Kelvin C Luk
  • ,
  • Michelle-Lee Jones
  • ,
  • Rosmarie Siegrist-Johnstone
  • ,
  • Yoon Kow Young
  • ,
  • Edouard Kouassi
  • ,
  • Vladimir V Rymar
  • ,
  • Alain Dagher
  • ,
  • Abbas F Sadikot
  • ,
  • Julie Desbarats
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.
Original languageEnglish
JournalJournal of Experimental Medicine
Volume202
Issue5
Pages (from-to)575-81
Number of pages7
ISSN0022-1007
DOIs
Publication statusPublished - 2005

    Research areas

  • Aged, Animals, Antigens, CD95, Brain, Chromatography, High Pressure Liquid, Female, Flow Cytometry, Humans, Immunohistochemistry, Lymphoproliferative Disorders, MPTP Poisoning, Male, Mice, Mice, Mutant Strains, Middle Aged, Neurons, Parkinson Disease, Signal Transduction, Up-Regulation

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