Study Rationale:
Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). The level of this protein in the brain correlates with the risk of Parkinson's. Lowering the level of alpha-synuclein can protect the brain from damage, as shown in multiple pre-clinical models with Parkinson's features. These findings support the development of therapeutics that lower alpha-synuclein level in people with Parkinson's disease.
Hypothesis:
We hypothesize that by mapping-- locating on the DNA strand -- the genes that control alpha-synuclein levels in multiple cell lines we would be able to devise new methods of lowering alpha-synuclein levels.
Study Design:
CRISPR-associated protein 9 (Cas9) has emerged as a new and powerful tool for editing, i.e., removing or inserting, genes in mammalian cells. We will use this tool to look for genes that affect the production of alpha-synuclein in several types of cells that naturally express this protein. These data will be used to determine which genes control alpha-synuclein levels and how they do it. We will then validate the therapeutic relevance of those genes in in vitro models.
Impact on Diagnosis/Treatment of Parkinson's disease:
Reducing alpha-synuclein levels is a promising therapeutic strategy for Parkinson's disease. The proposed systematic approach to finding genes that regulate alpha-synuclein will reveal the full genetic network that controls the levels of this important protein. Analysis of these data will reveal multiple new targets for drug development.
Next Steps for Development:
We envisage two main directions for this work. Firstly, we would test if targeting these newly identified regulators will not only reduce alpha-synuclein level but also improve disease symptoms in pre-clinical models without severe side effects. Secondly, we would devise strategies for targeting these regulators in people with PD.