TY - JOUR
T1 - Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
AU - Vicente Miranda, Hugo
AU - Szego, Éva M.
AU - Oliveira, Luís M.A.
AU - Breda, Carlo
AU - Darendelioglu, Ekrem
AU - De Oliveira, Rita M.
AU - Ferreira, Diana G.
AU - Gomes, Marcos A.
AU - Rott, Ruth
AU - Oliveira, Márcia
AU - Munari, Francesca
AU - Enguita, Francisco J.
AU - Simões, Tânia
AU - Rodrigues, Eva F.
AU - Heinrich, Michael
AU - Martins, Ivo C.
AU - Zamolo, Irina
AU - Riess, Olaf
AU - Cordeiro, Carlos
AU - Ponces-Freire, Ana
AU - Lashuel, Hilal A.
AU - Santos, Nuno C.
AU - Lopes, Luisa V.
AU - Xiang, Wei
AU - Jovin, Thomas M.
AU - Penque, Deborah
AU - Engelender, Simone
AU - Zweckstetter, Markus
AU - Klucken, Jochen
AU - Giorgini, Flaviano
AU - Quintas, Alexandre
AU - Outeiro, Tiago F.
N1 - Funding Information:
Authors were supported by: H.V.M. (Funda?a? para a Ci?ncia 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).
Publisher Copyright:
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - alpha-synuclein
KW - glycation
KW - neurodegeneration
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85019609948&partnerID=8YFLogxK
U2 - 10.1093/brain/awx056
DO - 10.1093/brain/awx056
M3 - Article
C2 - 28398476
AN - SCOPUS:85019609948
SN - 0006-8950
VL - 140
SP - 1399
EP - 1419
JO - Brain
JF - Brain
IS - 5
ER -