Investigating bacterial contributions and novel inhibitors to enhance levodopa efficacy in Parkinson's disease

Parkinson's disease (PD) is a brain disorder that gradually reduces dopamine levels, causing symptoms like tremors and stiffness. The most common treatment involves levodopa, a precursor that the body converts into dopamine. However, an enzyme called dopa decarboxylase (DDC) can convert levodopa into dopamine before it reaches the brain. To prevent this, levodopa is given with a DDC inhibitor. Yet, not all patients respond equally. One reason for this variation is the presence of certain gut bacteria that carry an enzyme called tyrosine decarboxylase (TDC), which also converts levodopa into dopamine, unaffected by the DDC inhibitor.In my PhD thesis, we investigated this problem. Using advanced computer simulations, we compared the structure of the human enzyme DDC with the bacterial enzyme TDC. Then, in experiments with rats, we tried increasing the levels of the existing DDC inhibitors to see if they could also block TDC. Unfortunately, this approach didn’t work. Next, we tested a variety of chemical compounds to see if any could inhibit TDC effectively. We identified a few promising candidates. However, we still need to test whether these compounds might also affect the human enzyme DDC and whether they are safe for use in people.This research is a step forward in the ongoing quest to improve treatments for Parkinson's disease. While there’s still work to be done, the insights gained from these studies bring us closer to a solution that could make a real difference in the lives of those affected by this challenging condition.

Dissertation: https://hdl.handle.net/11370/6282a31b-c3d0-45fc-ae53-03b96ac4157e