The Role of Tumor Necrosis Factor (TNF) in Microglial Activation and Progressive Degeneration of Dopaminergic Neurons

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). A number of studies have implicated chronic inflammation in the pathophysiology of PD; however, it is unclear which inflammatory mechanisms directly contribute to neuronal loss in PD. A number of cytokines, including TNF, are elevated in post-mortem brain and cerebrospinal fluid of patients with PD. Previous studies from our group have shown that blocking solTNF signaling at the time of a unilateral 6-OHDA striatal lesion attenuated behavioral deficits and the acute loss of dopaminergic neuron loss by 50%. However, a critical question of clinical relevance is whether delayed solTNF signaling inhibition can prevent the progressive loss of DA neurons that occurs after a CNS insult. I report here that a single intranigral injection of a lentivirus encoding a dominant negative TNF inhibitor delivered 2 weeks after an intrastriatal 6-OHDA lesion attenuated microgliosis in SNpc and halted the progressive loss of nigral DA neurons and the associated locomotor deficits. Given the potential contribution of microglial activation to PD and the suggestion that anti-TNF therapies in the CNS may exert neuroprotective effects on vulnerable dopaminergic neuron populations, I also investigated the role of TNF in regulating microglia effector functions to gauge the potential detrimental effects of anti-TNF therapies on the microglia functional response. I found that microglia from TNF-null mice produced reduced protein levels of cytokines and chemokines in response to LPS stimulation and they displayed no cytotoxic effects on dopaminergic neuroblastoma MN9D cells when activated in vitro. I also demonstrated that microglia isolated from TNF-null mice failed to display the expected morphological changes in response to LPS stimulation, including enhanced perinuclear expression of the activation marker CD45. My results suggest that TNF plays a critical role in microglia activation, regulation of several microglia effector functions and is the primary microglia-derived inflammatory factor that compromises survival of dopaminergic neurons. Furthermore, these studies suggest that TNF-dependent neuroinflammation directly contributes to the delayed and progressive degeneration of nigral DA neurons after neurotoxic injury and further validates solTNF as a potential therapeutic target in PD.