Chemical Chaperones Reduce Aggregate Formation and Cell Death Caused by the Truncated Machado–Joseph Disease Gene Product with an Expanded Polyglutamine Stretch

doi:10.1006/nbdi.2002.0502

Neurobiology of Disease

Volume 10, Issue 2, July 2002, Pages 88-99

https://doi.org/10.1006/nbdi.2002.0502 Get rights and content

Abstract

Machado–Joseph disease/spinocerebellar ataxia-3 (MJD/SCA-3) is an inherited neurodegenerative disorder caused by expansion of the polyglutamine stretch in the MJD gene-encoded protein ataxin-3. The truncated form of mutated ataxin-3 causes aggregation and cell death in vitro and in vivo. Abnormal conformation and misfolding of the pathological protein are assumed critical to pathogenesis. To test this hypothesis, we transfected BHK-21 and Neuro2a cells transiently with N-terminal truncated ataxin-3 with an expanded polyglutamine stretch. We then studied the effects of organic solvent dimethyl sulfoxide (DMSO), cellular osmolytes glycerol, and trimethylamine N-oxide (TMAO) on aggregate formation and cell death. These reagents stabilize proteins in their native conformation and called chemical chaperones based on their influence on protein folding. Aggregate formation and cytotoxicity induced by truncated expanded ataxin-3 were reduced by exposing cells to these chemical chaperones. Our results indicate the potentially useful therapeutic strategy of the chemical chaperones in preventing cell death in MJD.

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Regular ArticleChemical Chaperones Reduce Aggregate Formation and Cell Death Caused by the Truncated Machado–Joseph Disease Gene Product with an Expanded Polyglutamine Stretch

Abstract

Biochem. Biophys. Res. Commun.

Neuron

Trends Genet.

Cell

J. Biol. Chem.

Biochem. Biophys. Acta

Neuron

Am. J. Hum. Genet.

Trends Biochem. Sci.

Cell

Cell

Blood

Brain Res. Bull.

Analysis of the role of heat shock protein (HSP) molecular chaperones in polyglutamine disease

J. Neurosci.

Mechanisms of chaperone suppression of polyglutamine disease: Selectivity, synergy and modulation of protein solubility in Drosophila

Hum. Mol. Genet.

Chaperone suppression of ataxin-1 aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1

Nature Genet.

High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells

Hum. Mol. Genet.

Regular Article
Chemical Chaperones Reduce Aggregate Formation and Cell Death Caused by the Truncated Machado–Joseph Disease Gene Product with an Expanded Polyglutamine Stretch