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  Glycation potentiates alpha-synuclein-associated neurodegeneration in synucleinopathies.

Vincente Miranda, H., Szego, E. M., Oliveira, L. M., Breda, C., Darendelioglu, E., de Oliveira, R. M., et al. (2017). Glycation potentiates alpha-synuclein-associated neurodegeneration in synucleinopathies. Brain, 140(5), 1399-1419. doi:10.1093/brain/awx056.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-29B4-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-29B8-1
Genre: Journal Article

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 Creators:
Vincente Miranda, H., Author
Szego, E. M., Author
Oliveira, L. M., Author
Breda, C., Author
Darendelioglu, E., Author
de Oliveira, R. M., Author
Ferreira, D. G., Author
Gomes, M. A., Author
Rott, R., Author
Oliveira, M., Author
Munari, F., Author
Enguita, F. J., Author
Simoes, T., Author
Rodrigues, E. F., Author
Heinrich, M., Author
Martins, I. C., Author
Zamolo, I., Author
Riess, O., Author
Cordeiro, C., Author
Ponces-Freire, A., Author
Lashuel, H. A., AuthorSantos, N. C., AuthorLopes, L. V., AuthorXiang, W., AuthorJovin, T. M.1, Author              Penque, D., AuthorEngelender, S., AuthorZweckstetter, M.2, Author              Klucken, J., AuthorGiorgini, F., AuthorQuintas, A., AuthorOuteiro, T. F., Author more..
Affiliations:
1Emeritus Group Laboratory of Cellular Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_578629              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: glycation, Parkinson’s disease, neurodegeneration, alpha-synuclein
 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.

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Language(s): eng - English
 Dates: 2017-04-102017-05
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1093/brain/awx056
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Title: Brain
Source Genre: Journal
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Pages: - Volume / Issue: 140 (5) Sequence Number: - Start / End Page: 1399 - 1419 Identifier: -