Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism

Abstract

Despite attracting the close attention of multiple researchers for the past 25 years, α-synuclein continues to be an enigma, hiding sacred truth related to its structure, function, and dysfunction, concealing mechanisms of its pathological spread within the affected brain during disease progression, and, above all, covering up the molecular mechanisms of its multipathogenicity, i.e. the ability to be associated with the pathogenesis of various diseases. The goal of this article is to present the most recent advances in understanding of this protein and its aggregation and to show that the remarkable structural, functional, and dysfunctional multifaceted nature of α-synuclein can be understood using the proteoform concept.

Keywords: aggregation; multifunctionality; synucleinopathies; α-synuclein.

Figure 1.. A time course of the development of interest in α-synuclein-related research.

Web of Science data related to the publications dedicated to α-synuclein: the cumulative number of publications for the past 26 years (pink area plot) and the annual number of publications dedicated to this protein (cyan bars).

Figure 2.. Proteoform concept as a prism for looking at and understanding α-synuclein.

Schematic representation of the proteoform concept using the analogy of a prism. Here, an “incident light” (α-synuclein gene, SNCA), while going through the proteoform “prism” (a set of mechanisms put forward to generate different proteoforms), is “diffracted”, giving rise to a “spectrum” of proteoforms (a set of chemically or structurally different forms of a protein) for conducting different functions.