The Novel Hydroxylamine Derivative NG-094 Suppresses Polyglutamine Protein Toxicity in Caenorhabditis elegans

László Vígh,Maude Muriset,Pierre Haldimann,Pierre Goloubinoff

doi:10.1074/jbc.m111.234773

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.

Highlights

Aberrant protein folding leading to the formation of toxic protein conformers and aggregates causes several human neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer, Parkinson, and Huntington diseases [1, 2]
NG-094 Enhances Heat-induced Accumulation of heat-shock proteins (HSPs)—To determine whether NG-094 acts as a co-inducer of HSPs, we examined the effects of NG-094 on the expression of a set of HSP genes in Q0 and Q35 animals that were subjected or not to a heat-shock (HS) treatment. Quantitative RT-PCR (qPCR) analyses revealed that a
These findings suggest that the cytoprotective effect of NG-094 is related, at least in part, to the capacity of the drug to potentiate the activation of stress-inducible HSP genes when the expression of specific molecular chaperones is needed to maintain or restore proteostasis

Summary

Introduction

Aberrant protein folding leading to the formation of toxic protein conformers and aggregates causes several human neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer, Parkinson, and Huntington diseases [1, 2]. We used a C. elegans model system of polyQ diseases, in which the expression of polyQ expansions in body wall muscle cells causes animal paralysis that develops in a polyQ length- and age-dependent manner [20], to test the efficiency of treatment with a novel hydroxylamine derivative, NG-094, in conferring protection against polyQ proteotoxicity.

Results

Conclusion