Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of α-synuclein and β-amyloid and protect against amyloid-induced toxicity

Saviana Di Giovanni, Simona Eleuteri, Katerina E. Paleologou, Guowei Yin, Markus Zweckstetter, Pierre Alain Carrupt, Hilal A. Lashuel

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease (AD). There is considerable consensus that the increased production and/or aggregation of α-synuclein (α-syn) plays a central role in the pathogenesis of PD and related synucleinopathies. Current therapeutic strategies for treating PD offer mainly transient symptomatic relief and aim at the restitution of dopamine levels to counterbalance the loss of dopaminergic neurons. Therefore, the identification and development of drug-like molecules that block α-synuclein aggregation and prevent the loss of dopaminergic neurons are desperately needed to treat or slow the progression of PD. Here, we show that entacapone and tolcapone are potent inhibitors of α-syn and β-amyloid (Aβ) oligomerization and fibrillogenesis, and they also protect against extracellular toxicity induced by the aggregation of both proteins. Comparison of the anti-aggregation properties of entacapone and tolcapone with the effect of five other catechol-containing compounds, dopamine, pyrogallol, gallic acid, caffeic acid, and quercetin on the oligomerization and fibrillization of α-syn and Aβ, demonstrate that the catechol moiety is essential for the antiamyloidogenic activity. Our findings present the first characterization of the anti-amyloidogenic properties of tolcapone and entacapone against both α-synuclein and Aβ42 and highlight the potential of this class of nitro-catechol compounds as antiamyloidogenic agents. Their inhibitory properties, mode of action, and structural properties suggest that they constitute promising lead compounds for further optimization.

Original languageEnglish
Pages (from-to)14941-14954
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number20
DOIs
Publication statusPublished - 14 May 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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