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Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson's disease
Author(s) -
Sriram Krishnan,
Matheson Joanna M.,
Benkovic Stanley A.,
Miller Diane B.,
Luster Michael I.,
O'Callaghan James P.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0216fje
Subject(s) - mptp , dopaminergic , substantia nigra , neurodegeneration , neurotoxicity , proinflammatory cytokine , tumor necrosis factor alpha , neurotoxin , gliosis , parkinson's disease , microglia , neuroinflammation , receptor , cytokine , biology , dopamine , neuroscience , immunology , medicine , endocrinology , inflammation , disease , toxicity
ABSTRACT The pathogenic mechanisms underlying idiopathic Parkinson's disease (PD) remain enigmatic. Recent findings suggest that inflammatory processes are associated with several neurodegenerative disorders, including PD. Enhanced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)‐α, has been found in association with glial cells in the substantia nigra of patients with PD. To determine the potential role for TNF‐α in PD, we examined the effects of the 1‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydropyridine (MPTP), a dopaminergic neurotoxin that mimics some of the key features associated with PD, using transgenic mice lacking TNF receptors. Administration of MPTP to wild‐type (+/+) mice resulted in a time‐dependent expression of TNF‐α in striatum, which preceded the loss of dopaminergic markers and reactive gliosis. In contrast, transgenic mice carrying homozygous mutant alleles for both the TNF receptors (TNFR‐DKO), but not the individual receptors, were completely protected against the dopaminergic neurotoxicity of MPTP. The data indicate that the proinflammatory cytokine TNF‐α is an obligatory component of dopaminergic neurodegeneration. Moreover, because TNF‐α is synthesized predominantly by microglia and astrocytes, our findings implicate the participation of glial cells in MPTP‐induced neurotoxicity. Similar mechanisms may underlie the etiopathogenesis of PD.