An abnormally folded version of the protein alpha-synuclein forms characteristic clumps (Lewy bodies) in nerve cells in Parkinson's disease (PD). One possible reason for this is an age-related decrease in enzymes that degrade (break down) alpha-synuclein and are involved in the lysosome-autophagy system (LAS). During aging, changes in DNA methylation (the process of regulating gene expression) have been suggested to turn "off" LAS genes. This study focuses on TET3, an enzyme that can maintain its original methylation pattern and keep LAS genes turned "on." We predict that TET3 is reduced in aging, thereby increasing the risk for alpha-synuclein accumulation and PD, and that novel therapies can prevent this from occurring.
We hypothesize that TET3 activity is reduced in neurons during aging; this reduction could result in lower LAS activity and accumulation of alpha-synuclein, factors known to represent an increased risk for PD.
We will first determine if there is reduced functionality of TET3 aged individuals and in individuals with PD. We predict that LAS genes will display changes in their methylation patterns reflecting a decrease in TET3 activity. Second, we will reduce the amount of TET3 expression in cells and in pre-clinical models by mimicking the effects of aging and PD; we expect that a decrease in TET3 activity will lead to diminished LAS activity, which could subsequently result in higher levels of alpha-synuclein aggregation, as occurs in PD.
Impact on Diagnosis/Treatment of Parkinson's disease:
Modification of TET3 activity has the potential to impact the treatment of PD. There are known molecules that increase the activity of TET3 (e.g., Vitamin C), which could be further explored as therapeutic options for PD.
Next Steps for Development:
This study represents the first step in validating TET3 as a therapeutic target in PD. If successful, we will explore means to boost TET3 activity to restore the original pattern of LAS genes allowing for an improvement in the capacity of the neurons to handle abnormal proteins. This enhancement could result in a decreased accumulation of alpha-synuclein.