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. 2017 May 1;140(5):1399-1419.
doi: 10.1093/brain/awx056.

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

Hugo Vicente Miranda  1   2 , Éva M Szego  3 , Luís M A Oliveira  4   5 , Carlo Breda  6 , Ekrem Darendelioglu  6   7 , Rita M de Oliveira  1   2 , Diana G Ferreira  2   3 , Marcos A Gomes  2 , Ruth Rott  8 , Márcia Oliveira  2 , Francesca Munari  9   10 , Francisco J Enguita  2 , Tânia Simões  11 , Eva F Rodrigues  3 , Michael Heinrich  12 , Ivo C Martins  2 , Irina Zamolo  13 , Olaf Riess  13 , Carlos Cordeiro  14 , Ana Ponces-Freire  14 , Hilal A Lashuel  15 , Nuno C Santos  2 , Luisa V Lopes  2 , Wei Xiang  16 , Thomas M Jovin  5 , Deborah Penque  11 , Simone Engelender  8 , Markus Zweckstetter  9   10   17 , Jochen Klucken  12 , Flaviano Giorgini  6 , Alexandre Quintas  4 , Tiago F Outeiro  1   3   18
Affiliations

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

Hugo Vicente Miranda et al. Brain. .

Erratum in

  • Erratum to: Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies.
    Miranda HV, Szegő 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. Miranda HV, et al. Brain. 2021 Jul 28;144(6):e58. doi: 10.1093/brain/awab175. Brain. 2021. PMID: 34100910 No abstract available.

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.

Keywords: Parkinson’s disease; alpha-synuclein; glycation; neurodegeneration.

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