Subcellular structures called mitochondria perform many critical activities for brain cells. They generate enormous amounts of energy and remove the calcium that floods into neurons when they are active. In Parkinson’s disease (PD), mitochondria become overloaded with calcium, which triggers the opening of a pore in the mitochondrial membrane and the release of chemicals that initiate the cell-death program. At NRG Therapeutics, we are developing drugs that inhibit the opening of mitochondrial pores and thus prevent the death of dopamine-producing brain cells. However, the protein that these drugs target when they block the pore is unknown.
In this study, we will isolate and characterize the protein target with which our inhibitors interact to regulate mitochondrial pore opening. Identifying this target will facilitate progression of pore inhibitors into early clinical trials in people with Parkinson’s.
In the first phase of the project, we will incubate one of our pore inhibitors with isolated mitochondria and use a high-energy beam of light to fuse the molecule to the protein with which it interacts. This attachment will allow us to use the molecule as a “handle” with which we can selectively extract and isolate its protein partner. Using advanced techniques in biochemistry and molecular biology, we will identify the protein and then increase — and decrease — its concentration in mitochondria to confirm that it can regulate pore opening and cell death.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
NRG Therapeutics is developing mitochondrial pore inhibitors that can enter the brain and prevent the death of dopamine-producing cells. They hold significant potential to be developed as drugs that can protect the brain cells lost in Parkinson’s and slow or halt progression of the disease.
Next Steps for Development:
The next step in development is to test the effect of these drugs in pre-clinical models of PD. If they prove to be protective in these models, the drugs would then be progressed into studies to assess their safety and tolerability.