Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Abstract

The synucleins are a family of natively unfolded (or intrinsically unstructured) proteins consisting of α-, β-, and γ-synuclein involved in neurodegenerative diseases and cancer. The current number of publications on synucleins has exceeded 16.000. They remain the subject of constant interest for over 35 years. Two reasons explain this unchanging attention: synuclein's association with several severe human diseases and the lack of understanding of the functional roles under normal physiological conditions. We analyzed recent publications to look at the main trends and developments in synuclein research and discuss possible future directions. Traditional areas of peak research interest which still remain high among last year's publications are comparative studies of structural features as well as functional research on of three members of the synuclein family. Another popular research topic in the area is a mechanism of α-synuclein accumulation, aggregation, and fibrillation. Exciting fast-growing area of recent research is α-synuclein and epigenetics. We do not present here a broad and comprehensive review of all directions of studies but summarize only the most significant recent findings relevant to these topics and outline potential future directions.

Keywords: Parkinson’s disease; SNARE-complex; epigenetic; histones; methylation; phytochemicals; protein aggregation; protein trafficking; synucleinopathies; α-, β- and γ-synuclein.

Figure 1

The core sections of the seven amino-terminal repeats (KTKEGV motive) are shown as dark grey bars in α and γ-synucleins. These motives are located between amino acids 7–87 of human α- and γ-synuclein. β-Synuclein has only six such repeats. Positively charged regions are shown in light gray, hydrophobic regions are blue, and negatively charged regions are light brown. In α-synuclein the non-amyloid-β component (NAC) is shown, containing amino acids 61–95, playing a key role in aggregation in vitro. The absence of this region in β-synuclein decreases its tendency to aggregate. Amino acids 71VTGVTAVAQKTV82 are the most essential for α-synuclein aggregation [8,9]; it is. This domain is partly absent in β-synuclein and to some extent conserved in γ-synucleins, which might clarify why both homologs of α-synuclein are not aggregation prone as α-synuclein. Some missense mutations predisposing to diseases (A⁵³E, A⁵³T, A³⁰P, E⁴⁶K, H⁵⁰Q, T⁷²M, and E⁸³Q) are displayed as blue letters above and under the α-synuclein image (Modified from [10]). At the upper left corner N-terminal acetylation of α-synuclein is shown, which slows down its aggregation and changes the morphology of the aggregates [11,12].

Figure 2

Micelle-bound, tetrameric, and fibrillar α-synuclein. (A)—α-Synuclein is disordered under physiological conditions in solution. Disordered form is in equilibrium with a minor α-helical tetrameric form in the cytoplasm (B) α-Synuclein is α-helical when bound to a cell membrane (C) α-Synuclein may form polymorphic amyloid fibrils with unique arrangements of cross-β-sheet motifs. From Korneev et al. [30].