Study Rationale:
Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). It can attach itself and interact with fatty substances called lipids and fatty acids. Large, powerful research studies have revealed a connection between PD and proteins involved in lipid metabolism (production and breakdown in the cell). Our own studies have shown an interplay between lipids, fatty acids and alpha-synuclein. A lack of balance in alpha-synuclein production and breakdown greatly affects lipids and causes disease, and tweaking the body's lipid system (e.g., with a protein called stearoyl-CoA desaturase) promises to slow it. While interactions of alpha-synuclein and lipids are important in health and disease, there are currently no therapeutics targeting those interactions. We have previously identified stearoyl-CoA-desaturase as a potential therapeutic target for people with Parkinson's with excess alpha-synuclein or with changes in the alpha-synuclein gene (E46K mutations).
Hypothesis:
We hypothesize that interactions of alpha-synuclein and lipids could serve as drug targets in Parkinson's disease. This study aims to define these interactions and to transform them into therapeutic targets for PD.
Study Design:
We will conduct a detailed study of lipids that change when alpha-synuclein balance in the cell in altered. Excess of alpha-synuclein or mutations in the alpha-synuclein gene are known to cause Parkinson's. We will determine how they alter lipids and lipid interactions in the cell. Identified mechanisms will be studied further to define their contribution to PD and their potential to become therapeutic targets.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Given an increasing number of studies linking lipid-related genes with Parkinson's disease, it is important to assess how lipid changes in response to alpha-synuclein contribute to disease progression.
Next Steps for Development:
If this study successfully identifies a pathway (cellular process) that can be targeted to treat Parkinson's, the next steps would be to assess drugs that target the pathway, determine whether these drugs are able to travel to the brain and test them first in pre-clinical models and then in clinical trials.