Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
| Autor: | Carlos Cordeiro, Luís M. A. Oliveira, Ruth Rott, Deborah Penque, Tania Simões, Michael Heinrich, Francesca Munari, Ekrem Darendelioglu, Olaf Riess, Carlo Breda, Diana G. Ferreira, Thomas M. Jovin, Rita Machado de Oliveira, Luísa V. Lopes, Eva F. Rodrigues, Ivo C. Martins, Hugo Vicente Miranda, Jochen Klucken, Markus Zweckstetter, Hilal A. Lashuel, Alexandre Quintas, Márcia Oliveira, Nuno C. Santos, Marcos António Gomes, Tiago F. Outeiro, Irina Zamolo, Wei Xiang, Simone Engelender, Ana Ponces-Freire, Francisco J. Enguita, Éva M. Szegö, Flaviano Giorgini |
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| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Aging drug effects [Hippocampus] Glycosylation Parkinson's disease alpha-synuclein physiology [Hippocampus] pharmacology [Enzyme Inhibitors] metabolism [Neurodegenerative Diseases] Protein aggregation Hippocampus Transgenic pharmacology [Pyruvaldehyde] chemistry.chemical_compound Mice 0302 clinical medicine Ubiquitin Glycation Yeasts metabolism [alpha-Synuclein] Enzyme Inhibitors Cells Cultured Cultured biology drug effects [Induced Pluripotent Stem Cells] drug effects [Cell Differentiation] Neurodegeneration Methylglyoxal neurodegeneration Cell Differentiation Neurodegenerative Diseases Pyruvaldehyde 3. Good health Cell biology Genómica Funcional e Estrutural Biochemistry physiology [alpha-Synuclein] Drosophila Female drug effects [alpha-Synuclein] Cell Survival drug effects [Cell Survival] physiology [Cell Survival] Cells Induced Pluripotent Stem Cells Mice Transgenic toxicity [alpha-Synuclein] Protein Aggregation Pathological Alpha-synuclein 03 medical and health sciences metabolism [Protein Aggregation Pathological] drug effects [Glycosylation] Pathological medicine Animals Humans ddc:610 metabolism [Aging] Protein Processing Synucleinopathies Animal Post-Translational medicine.disease Protein Aggregation Rats nervous system diseases Parkinson’s disease glycation Disease Models Animal Protein Processing Post-Translational alpha-Synuclein 030104 developmental biology chemistry nervous system physiology [Yeasts] Disease Models biology.protein physiology [Induced Pluripotent Stem Cells] Neurology (clinical) drug effects [Yeasts] 030217 neurology & neurosurgery |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação instacron:RCAAP Brain Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) Brain 140(5), 1399-1419 (2017). doi:10.1093/brain/awx056 |
| DOI: | 10.1093/brain/awx056 |
| Popis: | © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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 Authors were supported by: H.V.M. (Fundação para a Ciência e Tecnologia (FCT), Portugal SFRH/BPD/64702/ 2009 and SFRH/BPD/109347/2015; EU FP7 project MEFOPA), L.M.A.O (FCT - SFRH/BD/23604/2005; CIRM-BMFB joint grant, 315050 AZ0101-31P6855), R.M.O. and T.S. (FCT SFRH/BPD/41416/2007; SFRH/ BPD/31209/2006); W.X. (Deutsche Forschungsgemeinschaft, SFB539/A3); C.B. and F.G. (Parkinson’s UK and the Medical Research Council, UK). S.E. is supported by Israel Academy of Sciences, Rappaport Family Institute for Research in the Medical Sciences, The Allen and Jewel Prince Center for Neurodegenerative Disorders of the Brain. T.F.O. (EMBO Installation Grant; Marie Curie IRG, Neurofold; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain; I.C.M. (FCT SFRH/BPD/74287/2010; Investigador FCT IF/00772/ 2013). This work was supported by: FCT PTDC/SAUNEU/105215/2008, PTDC/QUI/73430/2006, PTDC/SAUENB/117013/2010, PTDC/NEU-OSD/5644/2014; EU FP7 project MEFOPA; CIRM-BMFB joint grant (315050 AZ0101-31P6855); Max Planck Society; and European Union (NEURASYNC PITNGA-2009-238316). |
| Databáze: | OpenAIRE |
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