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  4. Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
 
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research article

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

Vicente Miranda, Hugo
•
Szego, Éva M
•
Oliveira, Luís M A
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2017
Brain : a journal of neurology

α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of α-synuclein, reducing membrane binding, impaired the clearance of α-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of α-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.

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Type
research article
DOI
10.1093/brain/awx056
Web of Science ID

WOS:000400069900026

Author(s)
Vicente Miranda, Hugo
•
Szego, Éva M
•
Oliveira, Luís M A
•
Breda, Carlo
•
Darendelioglu, Ekrem
•
de Oliveira, Rita M
•
Ferreira, Diana G
•
Gomes, Marcos A
•
Rott, Ruth
•
Oliveira, Márcia
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Date Issued

2017

Publisher

Oxford University Press

Published in
Brain : a journal of neurology
Volume

140

Issue

5

Start page

1399

End page

1419

Subjects

glycation

•

Parkinson's disease

•

neurodegeneration

•

alpha-synuclein

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LMNN  
Available on Infoscience
April 29, 2017
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/136622
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