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bioRxiv · 10.1101/2024.09.13.612928

Comprehensive mapping of the Interaction of levodopa and iron metabolism in Parkinson's disease

Wang, J.·Ekambaram, S.·Huang, X.·Mailman, R. B.·Proctor, E. A.·Dokholyan, N. V.
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Abstract

Levodopa remains the primary treatment for Parkinsons disease (PD), yet its long-term use has been associated with iron accumulation in the brain, a phenomenon linked to neurodegeneration. We utilize deep machine learning to determine plausible molecular mechanisms that may underlie the effects of levodopa on iron metabolism. Using the DRIFT platform, we performed a proteome-wide target identification of levodopa and uncovered significant interactions potentially involved in cellular iron transport. Pathway analysis revealed that levodopa may influence critical iron-related pathways, including the response of EIF2AK1 to heme deficiency, heme signaling, and ABC-family protein-mediated transport. These findings suggest that levodopa may contribute to iron dysregulation in PD by interacting with iron transporters and modulating iron-related pathways. Because levodopa is used at relatively high doses in PD, our findings provide new insight into secondary effects unrelated to being a precursor of dopamine. This highlights the need for careful consideration of its effects on iron metabolism as a consequence of use in the long-term management of PD. Further experimental validation is required to confirm these interactions, and also to explore potential strategies to mitigate iron-related side effects while preserving therapeutic efficacy.

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Wang, J., Ekambaram, S., Huang, X., Mailman, R. B., Proctor, E. A., Dokholyan, N. V.. 2024-09-19. Comprehensive mapping of the Interaction of levodopa and iron metabolism in Parkinson's disease. https://doi.org/10.1101/2024.09.13.612928

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