In Parkinson's disease (PD), the sticky protein alpha-synuclein clumps in the brain, causing cell death. Such toxic alpha-synuclein clumps can spread from cell to cell and multiply. It is not clear how cells take up toxic alpha-synuclein. We found that glycoproteins -- proteins with added chemical carbohydrate -- located on the outside of the cell may play a critical role in this process.
We hypothesize that alpha-synuclein recognizes specific glycoproteins on the cell surface and attaches itself to them, which gives it the ability to enter the cell.
In this study, we aim to understand how alpha-synuclein interacts with glycoproteins. This will clarify how PD-linked changes in the alpha-synuclein gene impact these interactions. We also aim to identify the glycoproteins to which alpha-synuclein attaches itself. To accomplish these goals, we will use biophysical methods to evaluate the strength of the interaction between alpha-synuclein and carbohydrates from cells. We will also identify glycoproteins that can attach themselves to alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson's disease:
If successful, our work may provide a new therapeutic target for the treatment of Parkinson's disease. This target will represent the interaction between alpha-synuclein and specific carbohydrates or glycoproteins found on the cell surface.
Next Steps for Development:
Next, we will search for molecules that stabilize or destabilize interaction between alpha-synuclein and identified glycoproteins. Identification of these glycoproteins lays the groundwork for further studies in nerve cells that were genetically engineered to lack the identified glycoproteins. These findings could ultimately be confirmed in pre-clinical models of Parkinson's disease.