Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease

Abstract

α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer's disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases.

Keywords: amyloid aggregation; fibril; neurodegenerative disorders; oligomer; polymorph; synucleinopathies; α-synuclein.

Figure 1

Schematic representation of the process of amyloid formation according to a nucleation-conversion-polymerization model. This model has been proposed for the process of αS aggregation when triggered at conditions of heterogeneous primary nucleation [10]: the initially formed oligomers slowly convert into partially formed β-sheet oligomers that further elongate and generate fully-formed mature fibrils. Note that this is a very simplified linear representation of the real funnel-like conformational landscape of the process.

Figure 2

Schematic representation of the different processes that can take place during amyloid fibril formation. Oligomeric species, highlighted with circles for a better visualization, can be generated through primary nucleation (A), but also through fibril disaggregation (D) or secondary nucleation (E) processes. Fibril elongation (B) and fragmentation (C) are also represented.

Figure 3

Structural features of αS fibrils. (A) Representative atomic force microscopy (AFM) and (B) 3D cryo-EM reconstruction image of a sample of αS fibrils. Adapted from Figure 1B,C, Guerrero-Ferreira, R. et al. 2018, eLife, published under the Creative Commons Attribution 4.0 International Public License (CC BY 4.0; https://creativecommons.org/licenses/by/4.0/) [123]. (C) Summary of the structural differences of αS fibril polymorphs resolved by cryo-EM. Reproduced from Figure 4, Guerrero-Ferreira, R. et al. 2019, eLife, published under the Creative Commons Attribution 4.0 International Public License (CC BY 4.0; https://creativecommons.org/licenses/by/4.0/) [119,120].

Figure 4

Structural features of two structurally different types of αS oligomers. Some of the most detailed structural information on αS oligomers has been obtained by the use of enriched samples of structurally homogeneous oligomeric species that have been trapped by the addition of molecules that prevent the conversion of oligomers to fibrils (for example the molecule EGCG, that results in the accumulation of type-A* oligomers) or the induction of alternative amyloid pathways by the modulation of the solution conditions that result in the kinetic stabilization of oligomeric species (i.e., induction of homogeneous nucleation under limited hydration conditions such as lyophilization, which results in the formation of type-B* oligomers). (A,B) Typical morphology of type-A* oligomers (A) and type-B* oligomers (B) probed by AFM. (C,D) Structural models of type-A* oligomers (C) and type-B* oligomers (D) according to the information obtained from solution and ssNMR data (from Fusco et al., Science 2017, reprinted with permission from AAAS) [145]. (E) Morphology and 3D-reconstruction models of type-B* oligomers according to cryo-EM image analysis (reprinted from Chen et al., PNAS 2015) [103].