Study Rationale:
Research suggests that accumulation of faulty mitochondria (the “powerhouse” of the cell) or mutated forms of the protein alpha-synuclein in the brain contribute to the development of Parkinson’s disease. Enhancing the removal of these from the brain would likely help treat the disease. In normal brain cells, unwanted components can be tagged with a signal, called ubiquitin, which then triggers the degradation and elimination of these components. The investigators plan to identify enzymes that add ubiquitin (called ligases) to mitochondria and alpha-synuclein, or take it off (called DUBs). Know the identity of these enzymes will allow researchers to potentially regulate them in the brains of Parkinson’s patients.
Hypothesis:
The researchers propose that there are multiple, as yet undiscovered, ubiquitin ligases and DUBs that can regulate the degradation of mitochondria and alpha-synuclein in cells.
Study Design:
They will use a technique called RNA interference to individually deplete all the different ubiquitin ligases and DUBs from cells (over 600 enzymes). They will look to see how loss of each one of these affects the cellular amount of mitochondria and alpha-synuclein. The team will also determine which ubiquitin ligases are active in different regions of the brain using sensitive biochemical assays. Together, this will help them identify enzymes that regulate turnover of mitochondria and alpha-synuclein and understand which ones are active in the right areas of the brain to treat Parkinson’s.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This project will help identify regulators of mitochondrial and alpha-synuclein turnover in the brain. If we can find ways to turn them on (or off) to trigger degradation of mitochondria and alpha-synuclein in the brains of Parkinson’s patients, we can use them in the development of new treatments.
Next Steps for Development:
Once the team identifies which enzymes regulate ubiquin in mitochondria and alpha-synuclein, chemists will be able to design small molecules to target them. In this way drugs can be developed to help activate removal of faulty mitochondrial and alpha-synuclein to treat the disease.