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Brain. 2017 May 1;140(5):1399-1419. doi: 10.1093/brain/awx056.

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies.

Author information

1
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.
2
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
3
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.
4
Centro de Investigação Interdisciplinar Egas Moniz, Instituto Superior de Ciências da Saúde Egas Moniz, 2829-511 Monte de Caparica, Caparica, Portugal.
5
Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
6
Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
7
Bingol University, Science and Letters Faculty, Molecular Biology and Genetics Department, 12000, Bingol, Turkey.
8
Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
9
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
10
German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
11
Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.
12
Department of Molecular Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
13
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72074 Tuebingen, Germany.
14
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.
15
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.
16
Institute for Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
17
Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, 37075 Göttingen, Germany.
18
Max Plank Institute for Experimental Medicine, Goettingen, Germany.

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.

KEYWORDS:

Parkinson’s disease; alpha-synuclein; glycation; neurodegeneration

PMID:
28398476
DOI:
10.1093/brain/awx056
[Indexed for MEDLINE]

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