Small molecule inducers of heat-shock response reduce polyQ-mediated huntingtin aggregation. A possible therapeutic strategy

Item Type:	Article
Title:	Small molecule inducers of heat-shock response reduce polyQ-mediated huntingtin aggregation. A possible therapeutic strategy
Creators Name:	Herbst, M. and Wanker, E.E.
Abstract:	Enhancing cellular defense mechanisms against different kinds of stress may be an attractive therapeutic strategy for neurodegenerative diseases. In particular, inducing the expression of molecular chaperones might reduce the formation of misfolded proteins and toxic aggregates that occur in polyglutamine (polyQ) disorders such as Huntingtons disease. Geldanamycin, a natural substance that modulates Hsp90 function, was previously shown to induce a heat-shock response and to reduce polyQ aggregation in mammalian cells. However, because of toxic and unfavorable pharmacokinetic properties, geldanamycin is not suitable for clinical use. In this study we evaluated the effects of the pharmacologically improved geldanamycin derivatives 17-DMAG and 17-AAG on polyQ aggregation in mammalian cells. Quantitative RT-PCR and SDS-PAGE experiments revealed that 17-DMAG induces expression of the molecular chaperones Hsp40, Hsp70, and Hsp105 in mammalian cells and inhibits the formation of mutant huntingtin aggregates with higher efficiency than 17-AAG or geldanamycin itself. Induction of a heat-shock response and inhibition of polyQ aggregation occurred at nanomolar concentrations. We suggest that geldanamycin derivatives such as 17-DMAG should be considered for the development of a drug treatment for polyQ disorders and other neurodegenerative diseases involving protein aggregation.
Keywords:	Neurodegeneration, Polyglutamine Disease, Protein Aggregation, Geldanamycin, Quantitative PCR, Filter Retardation Assay, Immunofluorescence Microscopy, Animals
Source:	Neurodegenerative Diseases
ISSN:	1660-2854
Publisher:	Karger
Volume:	4
Number:	2-3
Page Range:	254-260
Date:	June 2007
Official Publication:	https://doi.org/10.1159/000101849
PubMed:	View item in PubMed

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