α‐Synuclein (αS) is a presynaptic small protein that has attracted much interest because its aggregation and accumulation in the form of amyloid fibrils is the hallmark of a range of neurodegenerative disorders, collectively referred to as synucleinopathies. Despite intense research on this protein since it was first identified two decades ago as the major component of the proteinaceous intracellular inclusion characteristics of Parkinson disease, there is still no consensus on the physiological function of the protein and much remains to be established on the molecular basis of its toxicity. Recently, important steps have been undertaken to identify the different conformational states that this protein is able to adopt and elucidate their role in physiological and pathological conditions.

Key Concepts

  • The physiological function(s) of α‐synuclein remains controversial, although recent evidences suggest a major regulatory role in synapsis.
  • At physiological conditions, α‐synuclein is in a dynamic equilibrium between a membrane‐bound α‐helical (likely multimeric) conformation and a cytosolic intrinsically disordered (monomeric) conformation.
  • α‐Synuclein aggregation and fibril formation likely play a central role in Parkinson disease and other neurodegenerative disorders.
  • Different strains or fibril polymorphs of α‐synuclein have different degrees of infectivity and might be associated with distinct types of pathologies.
  • Different mechanisms of formation of α‐synuclein amyloid aggregates have been observed in vitro, but their relative relevance in vivo remains unknown.
  • Recent studies support the idea that multiple aggregated species of α‐synuclein can be generated through diverse misfolding pathways during the process of amyloid aggregation and could play distinct roles during the development of disease.
  • Combined methods to target specifically different α‐synuclein conformations could potentially prevent α‐synuclein‐associated toxicity.

Keywords: α‐synuclein; synucleinopathies; Parkinson disease; neurodegeneration; misfolding; aggregation; amyloid; fibril; oligomer

Figure 1. Structure of the physiological state of αS. (a) Schematic representation of the sequence‐dependent features of αS. The primary sequence of αS can be divided into three regions: the N‐terminal, the non‐β amyloid component (NAC) and the C‐terminal. Although the NAC region has been demonstrated to be essential and sufficient for the formation of amyloid fibrils, all the disease‐associated point mutations reported so far lie in the N‐terminus of the protein (their location is indicated by orange arrows). The protein contains seven imperfect apolipoprotein‐like repeat motives in its first N‐terminal 100 residues (blue boxes) that result in the acquisition of an amphipathic α‐helical structure in this region upon binding to lipid membranes (blue line). αS is able to bind redox‐active metal ions such as Cu2+, for which three binding sites have been reported: a high‐affinity binding site involving the first nine residues at the N‐terminus and two low‐affinity binding sites in the vicinity of residues His50 and Asp121 (Moriarty et al.,) (green lines). In addition, the protein is able to adopt β‐sheet structure upon its self‐assembly into amyloid fibrils. The folding core of αS in the fibrillar state has been reported to fall within residues 30–100 (red line). (b) Illustration representing the mechanism of interaction of αS with lipid membranes associated with its physiological function. The protein is in dynamic equilibrium between the cytosolic and the lipid‐bound state. Upon interaction with lipid bilayers, three different regions of the protein can be differentiated according to their affinities and dynamics of binding: the first 25 N‐terminal residues (in blue), which are rigidly bound and anchored to the bilayer, the central region (residues 26–98; in grey), more dynamic whose interaction with the bilayer depends strongly on the lipid composition, and a C‐terminal fragment (in green), which does not interact strongly with the bilayer and thus remains unstructured in the lipid‐bound state. (b) Reproduced with permission from Fusco et al. 2014 © Nature Publishing Group.
Figure 2. Mechanisms of formation of amyloid aggregates. There are generally two main processes that generate new aggregates: primary nucleation processes, where new aggregates form at a rate dependent only on the concentration of monomeric species, and secondary processes, where the new aggregates are formed at a rate dependent on the concentration of existing fibrils, being fibril fragmentation and secondary nucleation the most relevant secondary processes (Cohen et al.,). An additional mechanism typically involved in the processes of fibril formation, but that does not generate new aggregates per se is fibril elongation (that is typically associated with ‘fibril seeding’). The formation of oligomeric species in αS (highlighted with red circles) has been reported in primary nucleation processes (Cremades et al.,) and might also occur in fibril surface‐catalysed secondary nucleation processes as recently described for Aβ42 (Cohen et al.,). The primary nucleation of αS has been suggested to follow a nucleation‐conversion‐polymerisation mechanism, where αS monomeric molecules assemble initially into primarily disordered oligomers that slowly convert into more stable, β‐sheet oligomers that ultimately convert into amyloid fibrils by further growth and rearrangement (Cremades et al.,; Iljina et al.,).
Figure 3. Structures of aggregates with cross‐β architecture. (a) Example of the structure of an amyloid fibril. The structural architecture shown in yellow is one of the polymorphs of a 11‐residue fragment of transthyretin at atomic resolution obtained by the combination of cryo‐electron microscopy and solid‐state NMR. Reproduced from Fitzpatrick et al. 2013 © The National Academy of Sciences. (b) Structural organisation of αS into amyloid fibrils. Different structural organisations have been proposed, although most experimental data are consistent with a β‐serpentine topology (left image; Reproduced from Vilar et al. 2008 © The National Academy of Sciences), where αS monomers adopt an antiparallel in‐register β‐sandwich fold. More recently, a high‐resolution structure of a fibrillar form of full‐length αS has revealed a Greek‐key topology (right image; figure created using pdb 2n0a, Tuttle et al.,), where αS monomers assemble similarly as in the β‐serpentine topology, but with a more complex folding. (c) Outline of the structure of a class of toxic amyloid αS oligomer. The figure on the right represents a three‐dimensional cryo‐EM image reconstruction of a toxic oligomeric form of αS that is kinetically trapped during the formation of amyloid fibrils. The images shown in grey are representative of the side views (top) and end‐on views (bottom) of this structural class of oligomers. The images in blue show two orthogonal views, side (left) and end‐on (right), of the 3D reconstruction of the oligomer, showing the cylindrical architecture of the type observed for αS fibrils despite having only ca. 50% of the β‐sheet content of the latter and a different β‐strand arrangement. Reproduced from Chen et al. 2015 © The National Academy of Sciences.
Figure 4. Representation of a putative energy surface for the amyloid aggregation process. The energy landscape for the formation of amyloid aggregates is likely to be rugged and to be characterised by large numbers of degenerate energy states with significant energy barriers between different regions of the conformational space. The consequence of such a landscape is the existence of multiple pathways with multiple oligomeric species. Some pathways will generate oligomeric species that are only transient and that rapidly elongate and convert into fibrils (e.g. the pathway depicted in yellow), but other pathways will generate oligomeric species that are trapped in local minima and, therefore, accumulate (e.g. the pathway depicted in red). These oligomers present a structural configuration that is not optimal for elongation and therefore could only transform into fibrils after major structural rearrangements that are likely to be slow (dashed red arrows). Reproduced from Cremades and Dobson (2017) Elsevier.


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Further Reading

Chiti F and Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annual Review of Biochemistry 86: 27–68.

Goedert M, Spillantini MG, Del Tredici K and Braak H (2013) 100 years of Lewy pathology. Nature Reviews. Neurology 9: 13–24.

Lashuel HA, Overk CR, Oueslati A and Masliah E (2013) The many faces of alpha‐synuclein: from structure and toxicity to therapeutic target. Nature Reviews. Neuroscience 14: 38–48.

Uversky VN (2017) Looking at the recent advances in understanding alpha‐synuclein and its aggregation through the proteoform prism. F1000Res 6: 525.

Villar‐Piqué A, Lopes da Fonseca T and Outeiro TF (2016) Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies. Journal of Neurochemistry 139 (Suppl 1): 240–255.

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Cremades, Nunilo(Oct 2017) Alpha‐Synuclein. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027216]