On levodopa interactions with brain disease amyloidogenicproteins at the nanoscale

The cerebral accumulation of α-synuclein (α-Syn) and amyloid β-1−42 (Aβ-42) proteins is known to play a key role in the pathology of Parkinson’s disease (PD). Currently, levodopa (L-dopa) is the first-line dopamine replacement therapy for treating bradykinetic symptoms (i.e., difficulty initiating physical movements), which become visible in PD patients. Using atomic force microscopy, we evidence at nanometer length scales the differential effects of L-dopa on the morphology of α-Syn and Aβ-42 protein fibrils. L-dopa treatment was observed to reduce the length and diameter of both types of protein fibrils, with a stark reduction mainly observed for Aβ-42 fibrils in physiological buffer solution and human cerebrospinal fluid. The insights gained on Aβ-42 fibril disassembly from the label-free nanoscale imaging experiments are substantiated by using atomic-scale molecular dynamics simulations. Our results indicate L-dopa-driven reversal of amyloidogenic protein aggregation, which might provide leads for designing chemical effector-mediated disassembly of insoluble protein aggregates.