Skip to main content
Funded Studies

The Role of TNF-Mediated Dopaminergic Neurotoxicity in Parkinson's Disease: Novel Anti-TNF Biologics as Biochemical Tools and New Therapeutic Agents

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.

Final Outcome

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.


Researchers

  • Malú G. Tansey, PhD

    Gainesville, FL United States


Discover More Grants

Within the Same Funding Year

We use cookies to ensure that you get the best experience. By continuing to use this website, you indicate that you have read our Terms of Service and Privacy Policy.