Objective/Rationale:
Our preliminary findings indicate that the gut hormone, ghrelin, has a major impact on the functionality and protection of nigrostriatal dopamine neurons. We, therefore, will test the protective role of this circulating metabolic hormone on dopamine neurons under conditions mimicking Parkinson’s disease.
Project Description:
Based on our preliminary observations and pilot studies, we hypothesize that the circulating metabolic hormone, ghrelin, protects dopamine neurons during cellular stress and that this effect of ghrelin is mediated, at least in part, by a mitochondrial protein, UCP2. Thus, in the proposed aim, we will determine whether ghrelin signaling is an important mechanism by which dopamine cells of mice are protected against toxicity induced by a chemical, MPTP, that has effects on the brain mimicking Parkinson’s disease. Further, we will also test if ghrelin requires the mitochondrial protein, UCP2, to exert its neuroprotective effects.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We will move these investigations forward to a non-human primate model and ultimately (and rapidly) to humans. Ghrelin mimetics have been generated by several leading pharmaceutical companies, including Pfizer, Merck and Eli Lilly. These companies have been pursuing ghrelin as a therapeutic target from the perspective of metabolic disorders. Currently, numerous ghrelin-like compounds have been emerging from human trials. Thus, there will be a rapid translation of our findings to humans.
Anticipated Outcome:
We plan top provide compelling evidence that the gut hormone, ghrelin, is a promising to target for drug development to decrease the vulnerability of dopamine neurons in the course of Parkinson’s disease.
Final Outcome
Dr. Horvath published results of his work in the Journal of Neuroscience in November 2009. The team found that ghrelin is protective of dopamine neurons. Working in mice that received ghrelin supplementation and in mice that were deficient in ghrelin hormone and in the ghrelin receptor, the researchers found that when compared to controls, mice with impaired ghrelin action in the brain had more loss of dopamine. They also found that, in addition to its influence on appetite, ghrelin is responsible for direct activation of the brain's dopamine cells.
Because ghrelin originates from the stomach, it is circulating normally in the body, so it could be used to boost resistance to Parkinson's or to slow the development of the disease. In future work, Horvath and his team will try to determine ghrelin levels in both healthy individuals and Parkinson's patients. He will also determine whether altered ghrelin levels might serve as a biomarker of disease development and vulnerability.