Kinetic Mechanism of Heparin-Induced Fibrillation of α-Synuclein.

Abstract

Deposition of fibrillar aggregates of α-synuclein (αS) in the brain is a hallmark of αS-associated neurodegenerative diseases. Heparin, a structural analog of cell-surface heparan sulfate, modulates the kinetics of αS fibrillation and the morphology of the resulting fibrils. In this study, we investigated the kinetic mechanism of heparin-induced αS fibrillation using physicochemical techniques. Thioflavin T fluorescence and fibril-pelleting assays demonstrated that heparin greatly induces αS fibril formation and increases the mass of fibrillar αS in a concentration-dependent manner. Atomic force microscopy revealed that higher concentrations of heparin promote the formation of longer fibrils. These findings suggest that elongation of αS fibrils reaches a dynamic equilibrium during the plateau phase and that heparin shifts this equilibrium toward elongation. Considering the fibril dissociation process, we developed a kinetic model for heparin-induced αS fibrillation based on the process by which fibrillar αS inversely converts to a monomeric state. This model successfully captured the kinetic behavior of heparin-induced αS fibrillation and indicated that heparin promotes fibril growth by favoring elongation over dissociation. Overall, our study suggests the potential mechanism by which heparin promotes fibrillation of αS, highlighting the critical role of the equilibrium between fibril elongation and dissociation in αS fibrillation.