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The Journal of Neuroscience, February 25, 2004, 24(8):2045-2053; doi:10.1523/JNEUROSCI.4564-03.2004

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Neurobiology of Disease
Regulation of Dopaminergic Loss by Fas in a 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease

Shawn Hayley,^1,3 Stephen J. Crocker,¹ Patrice D. Smith,¹ Tanaya Shree,¹ Vernice Jackson-Lewis,² Serge Przedborski,² Matthew Mount,¹ Ruth Slack,¹ Hymie Anisman,³ and David S. Park¹

¹Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada K1H 8M5, ²The Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, and ³Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada K1S 5B6

Accumulating evidence suggests that apoptotic and inflammatory factors contribute to the demise of dopaminergic neurons. In this respect, Fas, a member of the tumor necrosis factor receptor family with proapoptotic and inflammatory functions, was reported to be elevated within the striatum and substantia nigra pars compacta (SNc) of Parkinson's disease (PD) patients. Accordingly, the present investigation evaluated the function of Fas in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Injection of MPTP increased nigral Fas expression, and mice lacking Fas displayed attenuated MPTP-induced SNc dopaminergic loss and microglial activation. In addition, Fas induction was blocked by expression of a dominant-negative c-Jun adenovirus that also protected dopamine neurons from MPTP-induced damage. Together, these data suggest the critical nature of the c-Jun-Fas signaling pathway in MPTP-induced neuronal loss. Although critical for degeneration of the soma, Fas deficiency did not significantly prevent the reduction of dopaminergic terminal fibers within the striatum or normalize the activation of striatal microglia and elevation of the postsynaptic activity marker FosB induced by denervation. Interestingly, Fas-deficient mice displayed a pre-existing reduction in striatal dopamine levels and locomotor behavior when compared with wild-type mice. Despite the reduced terminals, dopamine levels were not further suppressed by MPTP treatment in mutant mice, raising the possibility of a compensatory response in basal ganglia function in Fas-deficient mice.

Key words: Fas; neurodegeneration; cytokine; kinase; stress; dopamine

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Received Oct 8, 2003; revised December 19, 2003; accepted December 27, 2003.

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