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Title: Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
Authors: Miranda, Hugo Vicente
Szego, E´ va M.
Oliveira, Luı´s M. A.
Breda, Carlo
Darendelioglu, Ekrem
de Oliveira, Rita M.
Ferreira, Diana G.
Gomes, Marcos A.
Rott, Ruth
Oliveira, Ma´rcia
Munar, Francesca
Enguita, Francisco J.
Simoes, Tania
Rodrigues, Eva F.
Heinrich, Michael
Martins, Ivo C.
Zamolo, Irina
Riess, Olaf
Cordeiro, Carlos
Ponces-Freire, Ana
Lashuel, Hilal A.
Santos, Nuno C.
Lopes, Luisa V.
Xiang, Wei
Jovin, Thomas M.
Penque, Deborah
Engelender, Simone
Zweckstetter, Markus
Klucken, Jochen
Giorgini, Flaviano
Quintas, Alexandre
Outeiro, Tiago F.
First Published: 10-Apr-2017
Publisher: Oxford University Press
Citation: Brain, 2017, 140 (5), pp. 1399-1419
Abstract: 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.
DOI Link: 10.1093/brain/awx056
ISSN: 0006-8950
eISSN: 1460-2156
Embargo on file until: 10-Apr-2018
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.
Description: The file associated with this record is embargoed until 12 months after the date of publication. The final published version may be available through the links above.
Appears in Collections:Published Articles, Dept. of Genetics

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