On Levodopa interactions with brain disease proteins at the nanoscale
The cerebral accumulation of alpha-Synuclein (alpha-Syn) and amyloid beta-1-42 (Abeta-42) proteins are known to play a crucial role in the pathology of neurocognitive disorders such as Parkinson's disease (PD). Currently, Levodopa (L-dopa) is the dopamine replacement therapy for treating bradykinetic symptoms visible in PD patients. Here, we use atomic force microscopy to evidence at nanometer length scales the effects of L-dopa on the morphology of alpha-Syn and Abeta-42 protein fibrils. L-dopa treatment reduces the length and diameter of both types of protein fibrils, with a stark reduction observed for Abeta-42 both in physiological buffer and human spinal fluid. The insights gained on Abeta-42 fibril disassembly from the nanoscale imaging experiments are substantiated using atomic-scale molecular dynamics simulations. Our results reveal the mechanism governing L-dopa-driven reversal of protein aggregation, which may be useful in drug design of small molecule drugs for potentially treating neurocognitive disorders and provide leads for designing chemical effector-mediated disassembly of protein architectures.