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Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

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journal contribution
posted on 12.05.2017, 11:44 by Hugo Vicente Miranda, E´ va M. Szego, Luı´s M. A. Oliveira, Carlo Breda, Ekrem Darendelioglu, Rita M. de Oliveira, Diana G. Ferreira, Marcos A. Gomes, Ruth Rott, Ma´rcia Oliveira, Francesca Munar, Francisco J. Enguita, Tania Simoes, Eva F. Rodrigues, Michael Heinrich, Ivo C. Martins, Irina Zamolo, Olaf Riess, Carlos Cordeiro, Ana Ponces-Freire, Hilal A. Lashuel, Nuno C. Santos, Luisa V. Lopes, Wei Xiang, Thomas M. Jovin, Deborah Penque, Simone Engelender, Markus Zweckstetter, Jochen Klucken, Flaviano Giorgini, Alexandre Quintas, Tiago F. Outeiro
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.

History

Citation

Brain, 2017, 140 (5), pp. 1399-1419

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

AM (Accepted Manuscript)

Published in

Brain

Publisher

Oxford University Press

issn

0006-8950

eissn

1460-2156

Acceptance date

20/01/2017

Copyright date

2017

Available date

10/04/2018

Publisher version

https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awx056

Notes

The file associated with this record is embargoed until 12 months after the date of publication. The final published version may be available through the links above.

Language

en

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