Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/5439
Título: Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
Autor: 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
Munari, Francesca
Enguita, Francisco J.
Simões, Tânia
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.
Palavras-chave: Aging
Cell Differentiation
Cell Survival
Cells, Cultured
Disease Models, Animal
Enzyme Inhibitors
Induced Pluripotent Stem Cells
Mice, Transgenic
Neurodegenerative Diseases
Protein Aggregation, Pathological
Protein Processing, Post-Translational
Genómica Funcional e Estrutural
Data: 1-Mai-2017
Editora: Oxford University Press/Guarantors of Brain
Citação: Brain. 2017 May 1;140(5):1399-1419. doi: 10.1093/brain/awx056.
Resumo: 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.
Peer review: yes
URI: http://hdl.handle.net/10400.18/5439
DOI: 10.1093/brain/awx056
ISSN: 0006-8950
Versão do Editor: https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awx056
Aparece nas colecções:DGH - Artigos em revistas internacionais

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