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

Details

Serval ID
serval:BIB_2B27FFFA52DD
Type
Article: article from journal or magazin.
Collection
Publications
Title
The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans.
Journal
Journal of Biological Chemistry
Author(s)
Haldimann P., Muriset M., Vígh L., Goloubinoff P.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2011
Volume
286
Number
21
Pages
18784-18794
Language
english
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.
Keywords
Aging/drug effects, Aging/metabolism, Animals, Caenorhabditis elegans/metabolism, Caenorhabditis elegans Proteins/genetics, Caenorhabditis elegans Proteins/metabolism, Drug Evaluation, Preclinical, Humans, Hydroxylamines/chemistry, Hydroxylamines/pharmacology, Insulin-Like Growth Factor I/genetics, Insulin-Like Growth Factor I/metabolism, Muscle Proteins/metabolism, Neurodegenerative Diseases/drug therapy, Neurodegenerative Diseases/genetics, Peptides/genetics, Peptides/metabolism, Transcription Factors/genetics, Transcription Factors/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
18/05/2011 10:35
Last modification date
20/08/2019 14:10
Usage data