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The role of α-synuclein in neurodegeneration — An update

  • Review Article
  • Published:
Translational Neuroscience

Abstract

Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson’s disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Abbreviations

AD:

Alzheimer disease

ad:

autosomal-dominant

AGEP:

advanced glycation endproduct

ALP:

autophagy-lysosome pathway

ar:

autosomal-recessive

AS:

α-synuclein

Aβ:

β-amyloid

BS:

β-synuclein

CMA:

chaperone-mediated autophagy

CNS:

central nervous system

CSF:

cerebrospinal fluid

CSPα:

cystein string protein α

DA:

dopamine

DDLB:

diffuse dementia with Lewy bodies

DLB:

dementia with Lewy bodies

DNA:

desoxyribonucleic acid

Drp1:

dynamic-related protein 1

ER:

endpoplasmic reticulum

f:

familial

Fe:

iron

GBA:

glucocerebrosidase

GCI:

glial cytoplasmic inclusions

GS:

γ-synuclein

GSK-3β:

glycogen-synthase kinase-3β

GWAS:

genome wide association studies

Hsp:

heat-shock protein

iLBD:

incidental Lewy body disease

IMM:

inner mitochondrial membrane

LB:

Lewy body

LN:

Lewy neurite

LRRK2:

leucine-rich repeat kinase 2

LVB/AD:

Lewy body variant of Alzheimer disease

MAPK:

mitogen-activating protein kinase

MAPT:

tau protein gene

MBP:

myelin basic protein

MPTP:

1-methy l-4-phenyl-1, 2, 3, 6-tetrahydropyridine

mRNA:

messenger ribonucleic acid

MSA:

multiple system atrophy

MSA-C:

multiple system atrophy with predominant cerebellar ataxia

MSA-P:

multiple system atrophy with predominant parkinsonism

mtRNA:

mitochondrial ribonucleic acid

NAC:

non-amyloidogenic core

NCI:

neuronal cytoplasmic inclusion

nDNA:

nuclear DNA

NMR:

nuclear magnetic resonance

NSF:

N-ethylmaleimide-sensitive fusion protein

OMM:

outer mitochondrial membrane

OPCA:

olivopontocerebellar atrophy

OS:

oxidative stress

p:

phosphorylated

PD:

Parkinson disease

PDD:

Parkinson disease-dementia

PK:

proteinase K

ROS:

reactive oxygen species

s:

sporadic

Ser:

serin

SN:

substantia nigra

SNARE:

soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor

SNCA:

α-synuclein gene

SNCB:

β-synuclein gene

SNCG:

γ-synuclein gene

SND:

striato-nigral degeneration

Syn:

synuclein

tg:

transgenic

TH:

tyrosine hydroxylase

TNF:

tumor necrosis factor

TPPP:

tubulin-polymerization-promoting protein

tTG:

tissue transglutaminase

Ub:

ubiquitin

UBA:

ubiquitin-associated

UCHL1:

ubiquitin carboxy-terminal hydrolase L1

UPP:

ubiquitin-proteasome pathway

UPR:

unfolded protein response

UPS:

ubiquitin-proteasomal system

WT:

wild type

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    Kurt A. Jellinger

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Jellinger, K.A. The role of α-synuclein in neurodegeneration — An update. Translat.Neurosci. 3, 75–122 (2012). https://doi.org/10.2478/s13380-012-0013-1

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