The Role of TNF-Mediated Dopaminergic Neurotoxicity in Parkinson's Disease: Novel Anti-TNF Biologics as Biochemical Tools and New Therapeutic Agents
The Role of Inflammation in Parkinson's Disease, 2003
Loss of dopamine-producing neurons is a hallmark of Parkinson's disease and inflammation-driven oxidative stress is believed to play a significant role in this neurodegenerative process.
Strong evidence implicates the potent pro-inflammatory immune system protein Tumor Necrosis Factor-alpha (TNF) in the pathophysiology of PD. Specifically, TNF levels become rapidly elevated in all experimental models of PD and dopaminergic neurons are extremely sensitive to TNF. Clinically, early-onset PD patients often carry an allele in the TNF gene that makes them high TNF producers compared to non-affected individuals; and increased levels of TNF and TNF receptors are evident in postmortem brains and cerebrospinal fluid of PD patients.
We hypothesize that in PD, TNF-driven inflammatory responses play an important role in pathogenesis and progression of the disease. Consistent with this idea, a new model of PD has been described in which an activator of TNF, chronically infused into the brain of a rat model of PD at low concentrations, results in activation of immune surveillance cells in the brain as well as in delayed degeneration of dopaminergic neurons.
My collaborators and I propose studies to provide new and critical mechanistic information on the nature of the TNF-dependent processes that contribute to dopamine degeneration.
In July 2004, at the one-year assessment of Dr. Tansey’s initial grant under the Foundation's Inflammation initiative, her group demonstrated that two-week intranigral infusion of our novel dominant-negative TNFs afforded significant in vivo neuroprotection against the delayed (week 8) and selective nigral DA neuron loss induced by intranigral infusion of low-dose lipopolysaccharide. An important question is whether dominant-negative TNFs could provide equal or similar neuroprotection in other models of PD.
Associate Professor of Physiology at Emory University School of Medicine
Location: Atlanta, Georgia, United States