Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

H. Vicente Miranda, É.M. Szego, L.M.A. Oliveira, C. Breda, E. Darendelioglu, R.M. De Oliveira, D.G. Ferreira, M.A. Gomes, R. Rott, M. Oliveira, F. Munari, F.J. Enguita, T. Simões, E.F. Rodrigues, M. Heinrich, I.C. Martins, I. Zamolo, O. Riess, C. Cordeiro, A. Ponces-FreireH.A. Lashuel, N.C. Santos, L.V. Lopes, W. Xiang, T.M. Jovin, D. Penque, S. Engelender, M. Zweckstetter, J. Klucken, F. Giorgini, A. Quintas, T.F. Outeiro

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51 Citations (Scopus)

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. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
Original languageEnglish
Pages (from-to)1399-1419
Number of pages21
JournalBrain
Volume140
Issue number5
DOIs
Publication statusPublished - 1 May 2017

Keywords

  • alpha-synuclein
  • glycation
  • neurodegeneration
  • Parkinson's disease
  • alpha synuclein
  • aminoguanidine
  • methylglyoxal
  • oligomer
  • recombinant protein
  • tenilsetam
  • aging
  • animal experiment
  • animal model
  • Article
  • cytotoxicity
  • degenerative disease
  • Drosophila
  • evoked response
  • hippocampal slice
  • human
  • human cell
  • human tissue
  • immunoblotting
  • immunocytochemistry
  • immunoprecipitation
  • in vitro study
  • in vivo study
  • induced pluripotent stem cell
  • long term potentiation
  • male
  • membrane binding
  • molecular genetics
  • mouse
  • nerve degeneration
  • neuropathology
  • nonhuman
  • priority journal
  • protein aggregation
  • protein expression
  • protein processing
  • rat
  • size exclusion chromatography
  • synaptic potential
  • synaptic transmission
  • synucleinopathy
  • ubiquitination

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  • Cite this

    Vicente Miranda, H., Szego, É. M., Oliveira, L. M. A., Breda, C., Darendelioglu, E., De Oliveira, R. M., Ferreira, D. G., Gomes, M. A., Rott, R., Oliveira, M., Munari, F., Enguita, F. J., Simões, T., Rodrigues, E. F., Heinrich, M., Martins, I. C., Zamolo, I., Riess, O., Cordeiro, C., ... Outeiro, T. F. (2017). Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. Brain, 140(5), 1399-1419. https://doi.org/10.1093/brain/awx056