title: Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies.
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.
authors.affiliation: CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vicente Miranda
authors.affiliation: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany.
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szego
authors.affiliation: Centro de Investigação Interdisciplinar Egas Moniz, Instituto Superior de Ciências da Saúde Egas Moniz, 2829-511 Monte de Caparica, Caparica, Portugal.|Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Luís M A
authors.initials: LMA
authors.lastname: Oliveira
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Breda
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.|Bingol University, Science and Letters Faculty, Molecular Biology and Genetics Department, 12000, Bingol, Turkey.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Darendelioglu
authors.affiliation: CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Rita M
authors.initials: RM
authors.lastname: de Oliveira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Ferreira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Gomes
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rott
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Márcia
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Munari
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Enguita
authors.affiliation: Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors.forename: Tânia
authors.initials: T
authors.lastname: Simões
authors.affiliation: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany.
authors.forename: Eva F
authors.initials: EF
authors.lastname: Rodrigues
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heinrich
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ivo C
authors.initials: IC
authors.lastname: Martins
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Zamolo
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Enzymology Group, Departamento de Quimica e Bioquimica, Centro de Quimica e Bioquimica, Faculdade de Ciencias da Universidade de Lisboa, Campo Grande, Edificio C8, 1749-016, Lisboa, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordeiro
authors.affiliation: Enzymology Group, Departamento de Quimica e Bioquimica, Centro de Quimica e Bioquimica, Faculdade de Ciencias da Universidade de Lisboa, Campo Grande, Edificio C8, 1749-016, Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Ponces-Freire
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Swiss Federal Institute of Technology Lausanne (EPFL), FSV-BMI AI 2137.1, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Nuno C
authors.initials: NC
authors.lastname: Santos
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Luisa V
authors.initials: LV
authors.lastname: Lopes
authors.affiliation: Institute for Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Jovin
authors.affiliation: Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors.forename: Deborah
authors.initials: D
authors.lastname: Penque
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, 37075 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.affiliation: Centro de Investigação Interdisciplinar Egas Moniz, Instituto Superior de Ciências da Saúde Egas Moniz, 2829-511 Monte de Caparica, Caparica, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Quintas
authors.affiliation: CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany.|Max Plank Institute for Experimental Medicine, Goettingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004330:Drosophila; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006031:Glycosylation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011765:Pyruvaldehyde / Q000494:pharmacology; D051381:Rats; D015003:Yeasts / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D011765:Pyruvaldehyde
keywords: Parkinson’s disease; alpha-synuclein; glycation; neurodegeneration