Glycation potentiates alpha-synuclein-associated neurodegeneration in synucleinopathies
Date
2017Author
Vicente Miranda, Hugo and Szego, Eva M. and Oliveira, Luis M. A. and
Breda, Carlo and Darendelioglu, Ekrem and de Oliveira, Rita M. and
Ferreira, Diana G. and Gomes, Marcos A. and Rott, Ruth and Oliveira,
Marcia and Munari, Francesca and Enguita, Francisco J. and Simoes, Tania
and Rodrigues, Eva F. and Heinrich, Michael and Martins, Ivo C. and
Zamolo, Irina and Riess, Olaf and Cordeiro, Carlos and Ponces-Freire,
Ana and Lashuel, Hilal A. and Santos, Nuno C. and Lopes, Luisa V. and
Xiang, Wei and Jovin, Thomas M. and Penque, Deborah and Engelender,
Simone and Zweckstetter, Markus and Klucken, Jochen and Giorgini,
Flaviano and Quintas, Alexandre and Outeiro, Tiago F.
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Show full item recordAbstract
alpha-Synuclein misfolding and aggregation is a hallmark in Parkinson's
disease and in several other neurodegenerative diseases known as
synucleinopathies. The toxic properties of alpha-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 alpha-synuclein
toxicity in vitro and in vivo, in Drosophila and in mice. Glycation
affected primarily the N-terminal region of alpha-synuclein, reducing
membrane binding, impaired the clearance of alpha-synuclein, and
promoted the accumulation of toxic oligomers that impaired neuronal
synaptic transmission. Strikingly, using glycation inhibitors, we
demonstrated that normal clearance of alpha-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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