Protein–protein interactions regulating α-synuclein pathology

Trends in Neurosciences, Volume 47, Issue 3, 209 - 226

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(24)00014-6

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies (LBs). The main proteinaceous component of LBs is aggregated α-synuclein (α-syn). However, the mechanisms underlying α-syn aggregation are not yet fully understood. Converging lines of evidence indicate that, under certain pathological conditions, various proteins can interact with α-syn and regulate its aggregation. Understanding these protein–protein interactions is crucial for unraveling the molecular mechanisms contributing to PD pathogenesis. In this review we provide an overview of the current knowledge on protein–protein interactions that regulate α-syn aggregation. Additionally, we briefly summarize the methods used to investigate the influence of protein–protein interactions on α-syn aggregation and propagation.

(A) Scheme of α-syn illustrating its three regions and their characteristics: the N terminus (magenta), the non-amyloid-β (non-Aβ) component (NAC) (yellow), and the C terminus (turquoise). (B) Typical α-syn aggregation curve from the thioflavin (ThT) fluorescence assay. Factors that promote aggregation can shorten the lag phase of the α-syn aggregation curve, increase the growth phase, and increase the fluorescence intensity of the plateau phase, while factors that inhibit aggregation lead to the opposite changes. (C) Schematic diagram of α-syn aggregation. In the presence of external factors, protein monomers undergo liquid–liquid phase separation (LLPS) mechanism, leading to the demixing and formation of phase-separated droplets. The phase-separated droplets grow as a result of fusion and Ostwald ripening. Within a droplet, there is a high concentration of α-syn, which facilitates the binding of α-syn molecules and triggers an abnormal solid transformation of the droplet into an amyloid hydrogel. Fibrils can adsorb α-syn monomers and continue to extend. Fibrils can also split into oligomers to form additional aggregation cores.