Oligomer dynamics for drug discovery against α-synuclein aggregation in Parkinson's disease

Abstract

The aberrant aggregation of α-synuclein in Parkinson’s disease and related synucleinopathies is a histological hallmark of these conditions, as well as a cytotoxic process with no known disease-modifying interventions. While many studies have sought to develop small molecules or other biologics that may abrogate fibril formation, it is becoming increasingly clear that the toxicity associated with α-synuclein aggregation may be linked to soluble oligomeric species that serve as precursors to mature fibrils. These intermediate species are transient, amorphous and highly heterogenous in solution, which has precluded the study of their population dynamics in the context of drug discovery and screening. This thesis will aim to leverage a combination of theoretical and experimental approaches to model the flux towards oligomeric species formation within the fibril amplification process of α-synuclein, and subsequently to employ this flux as a selection parameter in drug discovery. By using this approach, possible strategies will be investigated to reduce oligomeric species formation and show that a particularly effective approach is to design small molecules that bind to the autocatalytic fibril surface of α-synuclein in a structure-based approach. Overall, the thesis aims to demonstrate the viability of the prediction and targeting of oligomeric α-synuclein species during secondary nucleation as a drug discovery pipeline that yields more robust links to the in vitro profile of an α-synuclein aggregation inhibitor and its resulting effect on α-synuclein-mediated toxicity in Parkinson’s disease pathology.