Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson's disease

• DOI: 10.1096/fj.02-0216fje
• Publication Date: 2002-08-30T23:03:10Z
• Authors: Krishnan Sriram; Joanna M. Matheson; Stanley A. Benkovic; Diane B. Miller; Michael I. Luster; James P. O'Callaghan
• Keywords: Male; 0301 basic medicine; 570; Tyrosine 3-Monooxygenase; brain; Dopamine; Dopamine Agents; Models, Neurological; 610; Receptors, Tumor Necrosis Factor; Mice; 03 medical and health sciences; Glial Fibrillary Acidic Protein; Animals; Gliosis; RNA, Messenger; MPTP; Mice, Knockout; Tumor Necrosis Factor-alpha; neurodegeneration; MPTP Poisoning; Parkinson Disease; Corpus Striatum; 3. Good health; Mice, Inbred C57BL; Kinetics; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Cytoprotection; neuroprotection

ABSTRACTThe 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.