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  • Review Article
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Alpha-synuclein and neurodegenerative diseases

Key Points

  • Synucleins are abundant brain proteins, the physiological functions of which are poorly understood. The synuclein family consists of three members: α-, β- and γ-synuclein. α- and β-synuclein are concentrated in nerve terminals, whereas γ-synuclein seems to be present throughout nerve cells.

  • α-synuclein is present in Lewy bodies, the main neuropathological characteristic of Parkinson's disease (PD). This observation has led to the proposal that α-synuclein might be involved directly in the pathogenic processes that underlie PD and several other diseases; the identification of α-synuclein mutations leading to the appearance of genetic forms of PD in two different families has provided support for this idea.

  • The presence of α-synuclein in Lewy bodies has also been observed in other diseases, including dementia with Lewy bodies and multiple system atrophy. Other conditions, such as Alzheimer's disease, the parkinsonism-dementia complex of Guam and Hallervorden–Spatz disease, can be accompanied by the formation of α-synuclein-positive Lewy bodies; however, it is not an invariant feature of these diseases.

  • The mechanism by which α-synuclein accumulation leads to neurodegeneration is not completely understood. A leading hypothesis is that the ordered assembly of α-synuclein into filaments, which seems to be induced by oxidative stress, is both necessary and sufficient to cause degeneration. However, alternative ideas have not been ruled out, and it is possible that oligomeric α-synuclein molecules are toxic.

Abstract

In recent years, two developments have imparted a new direction to research on the aetiology and pathogenesis of Parkinson's disease. First, the discovery that a missense mutation in the α-synuclein gene is a rare genetic cause of Parkinson's disease. Second, the identification of the α-synuclein protein as the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of all cases of Parkinson's and several other diseases. The filamentous inclusions of multiple system atrophy are also made of α-synuclein. These findings have placed α-synuclein dysfunction at the centre of several common neurodegenerative diseases. Here, I review the molecular properties of the synucleins, the different diseases characterized by the accumulation of α-synuclein, and the possible mechanisms by which dysfunction of α-synuclein might lead to neurodegeneration.

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Figure 1: Sequence comparison of human α-synuclein, β-synuclein and γ-synuclein.
Figure 2: Mesencephalic dopamine pathways in the human brain.
Figure 3: The α-synuclein pathology of Parkinson's disease.
Figure 4: The α-synuclein pathology of multiple system atrophy.
Figure 5: Model of disease pathway in Parkinson's disease.

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Acknowledgements

I thank R. A. Crowther, R. Jakes and M. G. Spillantini for the photographs used in Figures 3 and 4, and for helpful discussions. I am grateful to N. P. Quinn for part of Box 2.

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DATABASE LINKS

Pick's disease

Parkinson's disease

Alzheimer's disease

Frontotemporal dementia

α-Synuclein

β-Synuclein

γ-Synuclein

Phospholipase D2

Casein kinase 1

Casein kinase 2

Synphilin-1

Monoamine oxidase B

DLB

Ubiquitin

Parkinsonism-dementia complex of Guam

Hallervorden–Spatz disease

UCHL1

PARK2

AR–JP

PARK3

PARK4

Olivopontocerebellar atrophy

Striatonigral degeneration

Shy–Drager syndrome

Glossary

MISSENSE MUTATION

A mutation that results in the substitution of an amino acid in a protein.

ANKYRIN

An adaptor molecule that couples membrane proteins to the spectrin-based membrane cytoskeleton.

COILED-COIL DOMAIN

A protein domain that forms a bundle of two or three α-helices. Whereas short coiled-coil domains are involved in protein interactions, long coiled-coil domains, which form long rods, occur in structural or motor proteins.

ADAPTOR MOLECULE

A protein that contributes to cellular function by recruiting other proteins to a complex. Such molecules often contain several protein–protein interaction domains.

BRADYKINESIA

A neurological condition characterized by a generalized slowness of motor activity.

PENETRANCE

The proportion of genotypically mutant organisms that show the mutant phenotype. If all genotypically mutant individuals show the mutant phenotype, then the genotype is said to be completely penetrant.

UBIQUITINATION

Attachment of the protein ubiquitin to lysine residues of other molecules, often as a tag for their rapid cellular degradation.

ORTHOSTATIC HYPOTENSION

A sudden fall in blood pressure that occurs when a person assumes a standing position.

INTERMEDIOLATERAL COLUMNS

Preganglionic sympathetic neurons that are located in the spinal cord at the level of segments T1–L3.

ONUF'S NUCLEUS

A sexually dimporphic nucleus in the spinal cord that innervates striated perineal muscles mediating contraction of the bladder in males and vaginal contractions in the female.

GLIOSIS

The process of producing of a dense fibrous network of neuroglia; includes astrocytosis — the proliferation of astrocytes in the area of a degenerative lesion.

ELECTRON DIFFRACTION

An effect observed when a narrow beam of electrons passes through a layer of material and is deflected. The effect, which is due to the wave-like nature of electrons, can be used to infer the structure of the material.

POLYGLUTAMINE DISEASES

Disorders characterized at the molecular level by CAG-trinucleotide-repeat expansions in a gene, which translate into an excess of glutamine repeats in the coded protein. A well-known example is Huntington's disease, which is caused by the presence of additional CAG repeats in the gene huntingtin.

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Goedert, M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2, 492–501 (2001). https://doi.org/10.1038/35081564

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