Dynamic structural flexibility of α-synuclein

Abstract

α-Synuclein is a conserved, abundantly expressed protein that is partially localized in pre-synaptic terminals in the central nervous system. The precise biological function(s) and structure of α-synuclein are under investigation. Recently, the native conformation and the presence of naturally occurring multimeric assemblies have come under debate. These are important deliberations because α-synuclein assembles into highly organized amyloid-like fibrils and non-amyloid amorphous aggregates that constitute the neuronal inclusions in Parkinson’s disease and related disorders. Therefore understanding the nature of the native and pathological conformations is pivotal from the standpoint of therapeutic interventions that could maintain α-synuclein in its physiological state. In this review, we will discuss the existing evidence that define the physiological states of α-synuclein and highlight how the inherent structural flexibility of this protein may be important in health and disease.

Mechanical and thermodynamic properties of Aβ42, Aβ40 and α-synuclein fibrils: A coarse-grained method to complement experimental studies

“…7 (top panel) shows that the probability P 0 of finding the fibrils in the native state is larger for the Aβ 40 and Aβ 42 when compared to α -syn at any given temperature. This result is in agreement with a differential calorimetry experiment where it is observed that T m for β -amyloid fibrils is larger than α -syn fibrils [65,66]. In terms of the single fibril the Aβ 40 (PDB id: 2MVX) with two-fold symmetry is the most stable at higher temperature (thermophilic character) among the other two-fold and three-fold β -amyloids.…”

Proteostasis of α-Synuclein and Its Role in the Pathogenesis of Parkinson’s Disease

“…The pathological gain of neurotoxicity related to α-Synuclein involves multiple biological processes. Initially, soluble α-Synuclein monomers form oligomers, then gradually accumulate into insoluble mature fibrils; eventually, α-Synuclein aggregates into large insoluble fibrils which is more toxic to neurons and can cause cell death and progressive motor impairment (Melki, 2015;Peelaerts et al, 2015;Mor et al, 2016;Karpowicz et al, 2019;Ma et al, 2019). The fibrillar form of α-Synuclein assemblies is capable of promoting aggregation of monomeric α-Synuclein in vitro and this phenomenon can spread across cells in a prion-like fashion in cell cultures and animal models (Karpowicz et al, 2019;Ma et al, 2019).…”

Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

“…The list of aSyn PTMs detected in the human brain has grown extensively in recent years, which highlights the physicochemical and structural flexibility of aSyn 11,12 . Some of these PTMs have been implicated in PD pathology -in particular the phosphorylation at Serine 129 (Ser129-p) and truncations of the C-terminus (CTT).…”