On Levodopa interactions with brain disease proteins at the nanoscale

Abstract The cerebral accumulation of α-Synuclein (α-Syn) and amyloid β-1-42 (Aβ-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 α-Syn and Aβ-42 protein fibrils. L-dopa treatment reduces the length and diameter of both types of protein fibrils, with a stark reduction observed for Aβ-42 both in physiological buffer and human spinal fluid. The insights gained on Aβ-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. Competing Interest Statement The authors have declared no competing interest.