Neuregulin-2â: A Novel Trophic Factor for Midbrain Dopamine Neurons

The continuing search for new and effective trophic factors as candidate therapeutics for treatment of Parkinson's disease is of great importance. This project will evaluate two proteins from the neuregulin family of growth factors as novel therapeutic agents in a well-established animal model of Parkinson's disease. Little is known of the actions of the neuregulins in the mature brain, and particularly in the dopaminergic nigrostriatal pathway, the crucial circuit that degenerates in Parkinson's disease. Work in our laboratory has shown that mRNA and protein for the functional neuregulin receptor are synthesized within the nigrostriatal system of rodents and primates, including humans, specifically by the midbrain dopaminergic neurons. Our recent studies indicate that the neuregulin-1 gene product GGF2 exerts neurotrophic and neuroprotective effects upon midbrain dopaminergic neurons developing in culture and stimulates dopamine release in the nigrostriatal system in vivo. Moreover, we have found that treatment with GGF2 partially protects dopaminergic cells against subsequent neurotoxin-induced degeneration in vivo and partially promotes behavioral recovery. Recent evidence, however, suggests that a protein derived from the neuregulin-2 gene, called NRG-2beta, may be a more potent or preferred ligand for the neuregulin receptor than GGF2 and, thus, could offer enhanced neuroprotection for midbrain dopamine cells. In the present research we will expand upon our initial findings for GGF2 to determine if infusion of NRG-2beta after injury can rescue or repair the damaged dopaminergic nigrostriatal system to a greater extent than GGF2. These studies will use a well-characterized pre-clinical model of Parkinson's disease and specific neuregulin infusion regimens. Overall, this project will assess and compare the potential therapeutic value of two neuregulin trophic factors for the treatment of Parkinson's disease, with the goal of identifying the best candidate for future preclinical testing.