Rationally Designed Variants of α-Synuclein Illuminate Its in vivo Structural Properties in Health and Disease

Abstract

α-Synuclein (αS) is a conserved and abundant neuronal protein with unusual structural properties. It appears to partition between folded and unstructured states as well as between membrane-bound and aqueously soluble states. In addition, a switch between monomeric and tetrameric/multimeric states has been observed recently. The precise composition, localization and abundance of the multimeric species are under study and remain unsettled. Yet to interfere with disease pathogenesis, we must dissect how small changes in αS homeostasis may give rise to Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and other human synucleinopathies. Rationally designed αS point mutations that prevent the protein from populating all states within its normal folding repertoire have continued to be instrumental in bringing new insights into its biochemistry in vivo. This review summarizes biochemical and cell biological findings about αS homeostasis from different labs, with a special emphasis on intact-cell approaches that may preserve the complex, metastable native states of αS.

A series of helical α-synuclein fibril polymorphs are populated in the presence of lipid vesicles

“…Regarding molecular determinants of αS-lipid interaction that may predetermine the formation of the structures we report, it has been proposed that lysine-rich positions within αS may interact with negatively charged lipid head groups, while hydrophobic regions may interact with membrane lipids, leading to an initial helical conformation 1,28,29 . Specifically, the central region of the protein (residues 26-97) has been shown to bind to lipid membranes and positive charge within the N-terminal region may also play a key role in mediating binding to anionic lipids 30,31 .…”

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

“…In addition, positivelycharged lysine residues (K) in the KTKEGV motifs interact with negatively-charged membrane lipid head groups [56]. Yet, the helix formation is imperfect and only transient because, e.g., polar threonine (T) residues are located in the hydrophobic half of the helix [57][58][59]. A recent in vitro study suggests that ␣Syn coming off the membrane may retain its fold and assemble into helical multimers [60] (see next chapter).…”

“…Beyond the differences in their respective intrinsic biochemical properties, the SDS-sensitive ∼58-60 kDa ␣Syn tetramers, also called ␣Syn 'multimers' [71], and the SDS-resistant ∼55-60 kDa ␣Syn species [108] also appear to possess markedly different functions. As a brief reminder, genetic destabilization of ␣Syn multimers in mice was recently shown to produce a phenotype reminiscent of PD [73], indicating a supportive or physiological function of ␣Syn multimers in healthy conditions [58]. Contrasting with this role, brain levels of SDS-resistant ∼55 kDa ␣Syn oligomers inversely correlated with episodic memory and semantic memory performance in subjects with AD [108].…”

Novel Mannitol-Based Small Molecules for Inhibiting Aggregation of α-Synuclein Amyloids in Parkinson's Disease

“…α-Syn is an intrinsically disordered protein which acquires a broad conformational diversity, presumably endowing it with the ability to play multiple functions (Mizuno et al, 2012; Wang et al, 2016). Yet, the exact role of α-Syn at physiological and pathological conditions is not fully understood (Bendor et al, 2013; Ghosh et al, 2015; Dettmer, 2018). An attractive therapeutic strategy toward synucleopathies would be to reduce formation of toxic oligomers and fibrils of α-Syn.…”