Abstract
α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson’s disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts as a molecular chaperone to inhibit αS aggregation. As a result of this assignation, βS has been largely understudied in comparison to αS. However, recent reports suggest that βS promotes neurotoxicity, implying that βS is involved in other cellular pathways with functions independent of αS. Here, we review the current literature pertaining to human βS in order to understand better the role of βS in homeostasis and pathology. Firstly, the structure of βS is discussed. Secondly, the ability of βS to (i) act as a molecular chaperone; (ii) regulate synaptic function, lipid binding, and the nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate in protein degradation pathways; (v) modulate intracellular metal levels; and (vi) promote cellular toxicity and protein aggregation is explored. Thirdly, the P123H and V70M mutations of βS, which are associated with dementia with Lewy bodies, are discussed. Finally, the importance of post-translational modifications on the structure and function of βS is reviewed. Overall, it is concluded that βS has both synergistic and antagonistic interactions with αS, but it may also possess important cellular functions independent of αS.
Highlights
Abstract: α-Synuclein is a small, unstructured, presynaptic protein expressed in the brain
The restoration of βS upregulated tyrosine hydroxylase (TH) and aromatic L-amino decarboxylase (AADC), in which both proteins regulate DA synthesis and form transient complexes with vesicular monoamine transporter-2 (VMAT-2). These results indicate the novel role of βS to improve DA uptake by initiating the formation of a complex between AADC, TH, and VMAT-2, which may confer an allosteric effect on the DA transporter (DAT) [63]
As an Intrinsically disordered proteins (IDPs), βS is unstructured and is malleable to interact with a variety of macromolecules and ligands under different cellular conditions
Summary
Disordered proteins (IDPs) are characterized by their inability to fold into a stable or well-defined three-dimensional structure [1]. IDPs and intrinsically disordered regions in proteins account for more than one-third of the human proteome [2]. Their abundance implies their importance in key cellular processes such as homeostasis and survival [3,4]. Considering their abundance and their involvement in crucial biological processes, mutations in thesetheir proteins or regions to disease, with approximately. 20% of Considering abundance and are theirlinked involvement in crucial biological processes, human disease mutations occurring within intrinsically disordered regions of proteins [6]. The primary amino acid sequence of synuof synucleins exhibits a tripartite organization, with a highly conserved. The intrinsically disordered nature of βS means that it can adopt multiple dynamic conformations, properties which underlie its various functions within the cell
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