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-Freire & 12 others H.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

Research output: Contribution to journalArticle

35 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

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Synucleins
Poisons
Drosophila
Post Translational Protein Processing
Synaptic Transmission
Neurodegenerative Diseases
Parkinson Disease
Molecular Biology
Yeasts
Pathology
Phenotype
Membranes
Brain
Pharmaceutical Preparations

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

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. ; Ponces-Freire, A. ; Lashuel, H.A. ; Santos, N.C. ; Lopes, L.V. ; Xiang, W. ; Jovin, T.M. ; Penque, D. ; Engelender, S. ; Zweckstetter, M. ; Klucken, J. ; Giorgini, F. ; Quintas, A. ; Outeiro, T.F. / Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. In: Brain. 2017 ; Vol. 140, No. 5. pp. 1399-1419.
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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. {\circledC} The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.",
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Vicente Miranda, H, Szego, ÉM, Oliveira, LMA, Breda, C, Darendelioglu, E, De Oliveira, RM, Ferreira, DG, Gomes, MA, Rott, R, Oliveira, M, Munari, F, Enguita, FJ, Simões, T, Rodrigues, EF, Heinrich, M, Martins, IC, Zamolo, I, Riess, O, Cordeiro, C, Ponces-Freire, A, Lashuel, HA, Santos, NC, Lopes, LV, Xiang, W, Jovin, TM, Penque, D, Engelender, S, Zweckstetter, M, Klucken, J, Giorgini, F, Quintas, A & Outeiro, TF 2017, 'Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies' Brain, vol. 140, no. 5, pp. 1399-1419. https://doi.org/10.1093/brain/awx056

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. / 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.; Ponces-Freire, A.; Lashuel, H.A.; Santos, N.C.; Lopes, L.V.; Xiang, W.; Jovin, T.M.; Penque, D.; Engelender, S.; Zweckstetter, M.; Klucken, J.; Giorgini, F.; Quintas, A.; Outeiro, T.F.

In: Brain, Vol. 140, No. 5, 01.05.2017, p. 1399-1419.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

AU - Vicente Miranda, H.

AU - Szego, É.M.

AU - Oliveira, L.M.A.

AU - Breda, C.

AU - Darendelioglu, E.

AU - De Oliveira, R.M.

AU - Ferreira, D.G.

AU - Gomes, M.A.

AU - Rott, R.

AU - Oliveira, M.

AU - Munari, F.

AU - Enguita, F.J.

AU - Simões, T.

AU - Rodrigues, E.F.

AU - Heinrich, M.

AU - Martins, I.C.

AU - Zamolo, I.

AU - Riess, O.

AU - Cordeiro, C.

AU - Ponces-Freire, A.

AU - Lashuel, H.A.

AU - Santos, N.C.

AU - Lopes, L.V.

AU - Xiang, W.

AU - Jovin, T.M.

AU - Penque, D.

AU - Engelender, S.

AU - Zweckstetter, M.

AU - Klucken, J.

AU - Giorgini, F.

AU - Quintas, A.

AU - Outeiro, T.F.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - alpha-synuclein

KW - glycation

KW - neurodegeneration

KW - Parkinson's disease

KW - alpha synuclein

KW - aminoguanidine

KW - methylglyoxal

KW - oligomer

KW - recombinant protein

KW - tenilsetam

KW - aging

KW - animal experiment

KW - animal model

KW - Article

KW - cytotoxicity

KW - degenerative disease

KW - Drosophila

KW - evoked response

KW - hippocampal slice

KW - human

KW - human cell

KW - human tissue

KW - immunoblotting

KW - immunocytochemistry

KW - immunoprecipitation

KW - in vitro study

KW - in vivo study

KW - induced pluripotent stem cell

KW - long term potentiation

KW - male

KW - membrane binding

KW - molecular genetics

KW - mouse

KW - nerve degeneration

KW - neuropathology

KW - nonhuman

KW - priority journal

KW - protein aggregation

KW - protein expression

KW - protein processing

KW - rat

KW - size exclusion chromatography

KW - synaptic potential

KW - synaptic transmission

KW - synucleinopathy

KW - ubiquitination

U2 - 10.1093/brain/awx056

DO - 10.1093/brain/awx056

M3 - Article

VL - 140

SP - 1399

EP - 1419

JO - Brain

JF - Brain

SN - 0006-8950

IS - 5

ER -