TNF: A Key Neuroinflammatory Mediator of Neurotoxicity and Neurodegeneration in Models of Parkinson’s Disease
Microglia activation and overproduction of inflammatory mediators in the CNS have been implicated in Parkinson’s disease (PD) . Epidemiological studies suggest that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) at lower doses is associated with lower incidence of idiopathic PD compared to non-NSAID users [2, 3, 4]. However, key molecular mediators of neurotoxicity that directly contribute to neurodegeneration have not been identified. A role for the pro-inflammatory cytokine tumor necrosis factor (TNF) has been implicated in PD (reviewed in ). Nigral midbrain dopaminergic (DA) neurons are extremely sensitive to TNF , and the CSF and post-mortem brains of patients with both diseases display elevated levels of TNF [7, 8]. Lastly, although no robust genetic association between TNF and development of PD has been demonstrated, a single nucleotide polymorphism (SNP) in the TNF promoter gene has been associated with a rare form of early-onset idiopathic PD . Using engineered dominant-negative TNF variants (DN-TNFs)  and the decoy TNF receptor etanercept, we investigated the extent to which TNF-dependent mechanisms are required for loss of DA neurons in vitro and in vivo in two different models of parkinsonism.
KeywordsTumor Necrosis Factor Tumor Necrosis Factor Production Tumor Necrosis Factor Signaling Nigral Degeneration Glia Culture
We thank D. E. Szykowski at Xencor for providing DN-TNF (XENP345) reagents for our studies and members of the Tansey Lab for useful discussions.
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