α-Synuclein oligomers in skin biopsy of idiopathic and monozygotic twin patients with Parkinson's disease.
Parkinson’s disease
monozygotic twins
proximity ligation assay
skin biopsy
α-synuclein oligomers
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 03 2020
01 03 2020
Historique:
received:
19
07
2019
revised:
22
11
2019
accepted:
02
12
2019
pubmed:
7
2
2020
medline:
7
7
2020
entrez:
7
2
2020
Statut:
ppublish
Résumé
A variety of cellular processes, including vesicle clustering in the presynaptic compartment, are impaired in Parkinson's disease and have been closely associated with α-synuclein oligomerization. Emerging evidence proves the existence of α-synuclein-related pathology in the peripheral nervous system, even though the presence of α-synuclein oligomers in situ in living patients remains poorly investigated. In this case-control study, we show previously undetected α-synuclein oligomers within synaptic terminals of autonomic fibres in skin biopsies by means of the proximity ligation assay and propose a procedure for their quantification (proximity ligation assay score). Our study revealed a significant increase in α-synuclein oligomers in consecutive patients with Parkinson's disease compared to consecutive healthy controls (P < 0.001). Proximity ligation assay score (threshold value > 96 using receiver operating characteristic) was found to have good sensitivity, specificity and positive predictive value (82%, 86% and 89%, respectively). Furthermore, to disclose the role of putative genetic predisposition in Parkinson's disease aetiology, we evaluated the differential accumulation of oligomers in a unique cohort of 19 monozygotic twins discordant for Parkinson's disease. The significant difference between patients and healthy subjects was confirmed in twins. Intriguingly, although no difference in median values was detected between consecutive healthy controls and healthy twins, the prevalence of healthy subjects positive for proximity ligation assay score was significantly greater in twins than in the consecutive cohort (47% versus 14%, P = 0.019). This suggests that genetic predisposition is important, but not sufficient, in the aetiology of the disease and strengthens the contribution of environmental factors. In conclusion, our data provide evidence that α-synuclein oligomers accumulate within synaptic terminals of autonomic fibres of the skin in Parkinson's disease for the first time. This finding endorses the hypothesis that α-synuclein oligomers could be used as a reliable diagnostic biomarker for Parkinson's disease. It also offers novel insights into the physiological and pathological roles of α-synuclein in the peripheral nervous system.
Identifiants
pubmed: 32025699
pii: 5727889
doi: 10.1093/brain/awaa008
pmc: PMC7089656
doi:
Substances chimiques
Synucleins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Twin Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
920-931Informations de copyright
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
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