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Title: Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
Author: Miranda, Hugo Vicente
Szego, Éva M.
Oliveira, Luís M. A.
Breda, Carlo
Darendelioglu, Ekrem
Oliveira, Rita M. de
Ferreira, Diana G.
Gomes, Marcos A.
Rott, Ruth
Oliveira, Márcia
Munari, Francesca
Enguita, Francisco J.
Simões, Tânia
Rodrigues, Eva F.
Heinrich, Michael
Martins, Ivo C.
Zamolo, Irina
Riess, Olaf
Cordeiro, Carlos
Freire, Ana Ponces
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.
Keywords: Glycation
Parkinson’s disease
Issue Date: 2017
Publisher: Oxford University Press
Citation: Brain 2017: 140; 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
Description: © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
Peer review: yes
DOI: 10.1093/brain/awx056
ISSN: 0006-8950
Publisher Version:
Appears in Collections:IMM - Artigos em Revistas Internacionais

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