Accumulation of the alpha-synuclein protein inside neurons in particular regions of the brain is one of the hallmarks of Parkinson’s disease. Studies suggest that lowering the production of alpha-synuclein could provide benefit to Parkinson’s patients and several pharmaceutical companies are working on developing drugs that will change the metabolism of alpha-synuclein. To advance the development of such drugs we will develop an assay that can measure the metabolism of alpha-synuclein in the brain of human subjects.
We will assess metabolism of alpha-synuclein by measuring the incorporation of a stable isotope labeled amino acid into the protein. Alpha-synuclein needs to be isolated from all the other proteins present in biological fluids and our initial studies will focus on developing methods for isolation of alpha-synuclein. We will perform these studies on tissue culture cells as well as cerebrospinal fluid from healthy human volunteers. The only way to detect the incorporation of the stable isotope into newly synthesized proteins is to weigh the proteins. If the protein contains the label it will contain 6 more neutrons than the unlabeled protein, detecting the presence of these 6 neutrons require a highly sensitive balance such as a mass spectrometer. Measuring the incorporation of the label into newly synthesized proteins will allow us to calculate the rate at which the protein is being produced in the brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our studies will give insights into the metabolism of alpha-synuclein in the human brain. As drugs are developed that target alpha-synuclein metabolism, this method could help test if such drugs are working in human patients and thus help with figuring out the optimal dosing and potentially speed the approval of such drugs.
We predict that we will be able to measure the rate of production and clearance of alpha-synuclein in the human brain.