Testing Whether Alpha-Synuclein is Modified by 4-hydroxy-2-nonenal in the Human Brain

Promising Outcomes of Original Grant:
The major goal of our grant application was to test whether a protein known as alpha-synuclein becomes toxic to dopamine-secreting nerve cells when it is modified by a particular chemical agent known as 4-hydroxy-2-nonenal. Using a pre-clincal model of Parkinson’s disease, we found that altering the alpha-synuclein protein such that this chemical modification is reduced significantly attenuates its toxicity.

Objectives for Supplemental Investigation: 
We propose to isolate alpha-synuclein protein from the human brain, and from a pre-clincal model and conduct analyses to test whether the chemical modification responsible for toxicity that occurs in pre-clincal models also occurs in the human brain. We also propose to test whether the modification that renders alpha-synuclein toxic in pre-clincal models is more abundant in the brains of individuals with Parkinson’s disease. Lastly, if the chemical modification is conserved in humans, we propose to initiate experiments to identify which part of the alpha-synuclein protein becomes modified in the human brain. These experiments will help to establish the validity of our findings to humans.

Importance of This Research for the Development of a New PD Therapy:
The chemical species that we believe is responsible for modifying alpha-synuclein and converting it to a toxic form, 4-hydroxy-2-nonenal, is an oxidatively damaged lipid. The formation of 4-hydroxy-2-nonenal can be prevented by treating pre-clincal models with known anti-oxidants. Moreover, the degradation of 4-hydroxy-2-nonenal can be enhanced by treatment with existing chemical agents. Thus, the chemical agents responsible for the prevention of 4-hydroxy-2-nonenal formation and for its enhanced breakdown represent potential therapeutic agents for preventing Parkinson’s disease, or delaying its progression.