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) [1]. 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 [5]). Nigral midbrain dopaminergic (DA) neurons are extremely sensitive to TNF [6], 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 [9]. Using engineered dominant-negative TNF variants (DN-TNFs) [10] 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.