The many faces of α-synuclein: from structure and toxicity to therapeutic target

Key Points

  • Recent studies of the structural and functional roles of α-synuclein show that this protein participates in synaptic vesicle transport.

  • Increased expression and/or accumulation of α-synuclein owing to genetic duplication, mutations or a failure in clearance may have roles in Parkinson's disease and related disorders.

  • Different conformers of α-synuclein, including oligomers, protofibrils and fibrils, may contribute to α-synuclein-mediated toxicity.

  • Recent studies suggest that the propagation and transmission of α-synuclein participate in the pathogenesis of Parkinson's disease.

  • Reducing α-synuclein expression, aggregation or propagation, or increasing the clearance of this protein all represent viable therapeutic strategies for combating Parkinson's disease and related disorders.

Abstract

Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism (or mechanisms) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.

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Figure 1: Functional properties of α-synuclein.
Figure 2: Biochemical structure of α-synuclein and its pathological distribution in Parkinson's disease, and a mouse model of Lewy body disease.
Figure 3: Cellular events controlling intracellular α-synuclein levels and possible therapeutic strategies to combat α-synuclein accumulation and transmission.
Figure 4: Mechanisms of α-synuclein aggregation and propagation.

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Acknowledgements

The authors acknowledge grant support from the US National Institutes of Health (grants AG5131, AG18440, AG022074 and NS044233 to E.M.), the Swiss National Science Foundation (grant #31003A_120653 to H.A.L.) and the Ecole Polytechnique Fédérale de Lausanne (European Research Council starting grant to H.A.L.).

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Correspondence to Eliezer Masliah.

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Glossary

Lewy body

An intraneuronal globular inclusion composed primarily of α-synuclein fibrils. Lewy bodies are characteristically found in Parkinson's disease, although they are also detectable in other neurodegenerative diseases, such as dementia with Lewy bodies.

Fibril

Mature fibrils are characterized by the following characteristics: a cross-β-sheet X-ray fibre diffraction pattern; β-sheet-rich circular dichroism and Fourier transform infrared spectroscopy (FTIR) spectra; binding to Congo red and Thioflavin-T/S; and a characteristic filamentous morphology (8–12nm in diameter and >1μm in length), as revealed by atomic force microscope and transmission election microscope imaging. α-synuclein can form fibrils of diverse morphologies depending on the solution conditions.

SNARE

Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptor.

Oilgomer

Oligomers comprise a number of smaller, identical units (monomers). In the context of α-synuclein oligomers, this term encompasses a wide range of species, ranging from low-molecular-weight species (including dimers, trimers and tetramers) to high-molecular-weight species (such as spherical, chain-like and annular structures.

Nuclei

Thermodynamically unstable oligomeric species that are capable of acting as sites for amyloid fibril growth.

Seed

A relatively stable entity (such as a fibril or fragmented fibril) that, when introduced into a solution containing monomeric subunits, serves as an effective nucleus and accelerates fibril formation (by eliminating the lag phase associated with nuclei formation) in a nucleation polymerization process.

Native state

The three-dimensional structure of the protein in its normal physiological milieu in the absence of any denaturing agents or conditions.

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Lashuel, H., Overk, C., Oueslati, A. et al. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14, 38–48 (2013). https://doi.org/10.1038/nrn3406

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