Study Rationale:
In Parkinson's disease (PD), death of dopamine-producing brain cells takes place mainly the substantia nigra pars compacta (SN) but not in the neighboring ventral tegmental area (VTA). Many studies explored differences between dopamine-producing cells of these two regions, but little was done to understand astrocytes, another type of brain cell, and their role in the disease. We recently discovered that VTA astrocytes contain a 230-fold excess of protein GDF15 and are capable of rescuing both SN and VTA dopamine-producing cells from death in an in vitro model of PD. GDF15, therefore, is a possible therapeutic.
Hypothesis:
We hypothesize that GDF15 has a neuroprotective effect and, therefore, can rescue dopamine-producing brain cells in SN and improve movement in a pre-clinical model of Parkinson's.
Study Design:
After we genetically engineer pre-clinical models of Parkinson's to produce either none or excess of GDF15 in the brain, we will evaluate the ability of GDF15 to protect their brain cells from death. Next, we will confirm the therapeutic potential of GDF15 in pre-clinical models of Parkinson's by infusing the drug directly into the brain. We will also study effects of GDF15 in stem cells with mutations (genetic changes) causing inherited PD. In addition to having these mutations, the cells will be treated with a toxic chemical capable of killing brain cells.
Impact on Diagnosis/Treatment of Parkinson's disease:
Confirming the ability of GDF15 to protect dopamine-producing cells of the SN region in models of PD will represent a significant step toward finding a cure for Parkinson's disease. Moreover, these findings could have major impact on our understanding of biology. Specifically, these findings might suggest that certain groups of brain cells are more susceptible to disease risk factors because of their environment and not because of their own properties.
Next Steps for Development:
In the future, it will be important to evaluate neuroprotective effects of GDF15 in other pre-clinical models before advancing this therapeutic candidate to human clinical trials.