The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans

Pierre Haldimann, Maude Muriset, L. Vígh, Pierre Goloubinoff

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Aggregation-prone polyglutamine (polyQ) expansion proteins cause several neurodegenerative disorders, including Huntington disease. The pharmacological activation of cellular stress responses could be a new strategy to combat protein conformational diseases. Hydroxylamine derivatives act as co-inducers of heat-shock proteins (HSPs) and can enhance HSP expression in diseased cells, without significant adverse effects. Here, we used Caenorhabditis elegans expressing polyQ expansions with 35 glutamines fused to the yellow fluorescent protein (Q35-YFP) in body wall muscle cells as a model system to investigate the effects of treatment with a novel hydroxylamine derivative, NG-094, on the progression of polyQ diseases. NG-094 significantly ameliorated polyQ-mediated animal paralysis, reduced the number of Q35-YFP aggregates and delayed polyQ-dependent acceleration of aging. Micromolar concentrations of NG-094 in animal tissues with only marginal effects on the nematode fitness sufficed to confer protection against polyQ proteotoxicity, even when the drug was administered after disease onset. NG-094 did not reduce insulin/insulin-like growth factor 1-like signaling, but conferred cytoprotection by a mechanism involving the heat-shock transcription factor HSF-1 that potentiated the expression of stress-inducible HSPs. NG-094 is thus a promising candidate for tests on mammalian models of polyQ and other protein conformational diseases.

Original languageEnglish
Pages (from-to)18784-18794
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number21
DOIs
Publication statusPublished - May 27 2011

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Hydroxylamine
Caenorhabditis elegans
Toxicity
Derivatives
Proteins
Heat-Shock Proteins
Animals
Cytoprotection
polyglutamine
Huntington Disease
Somatomedins
Glutamine
Paralysis
Neurodegenerative Diseases
Muscle Cells
Muscle
Disease Progression
Agglomeration
Aging of materials
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans. / Haldimann, Pierre; Muriset, Maude; Vígh, L.; Goloubinoff, Pierre.

In: Journal of Biological Chemistry, Vol. 286, No. 21, 27.05.2011, p. 18784-18794.

Research output: Contribution to journalArticle

Haldimann, Pierre ; Muriset, Maude ; Vígh, L. ; Goloubinoff, Pierre. / The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 21. pp. 18784-18794.
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