Exp Mol Med.
2007 Feb;39(1):38-46.
Heat shock protein 70 alters the endosome-lysosomal localization of huntingtin
- Affiliations
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- 1Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea. immanho@snu.ac.kr
- 2Department of Neurology, Seoul Medical Center, Seoul 135-090, Korea.
- 3Department of Biology, Sungshin Women's University, Seoul 136-742, Korea.
- 4Department of Biochemistry, Ilchun Molecular Medicine Institute MRC, Seoul National University, Seoul 110-799, Korea.
- 5Department of Anatomy, Seoul National University College of Medicine, Seoul 110-799, Korea.
- 6Brain Disease Research Center, Ajou University and Department of Neurology, University of British Columbia, Vancouver, Canada.
- 7Department of Craniomaillofacial Reconstructive Science, Nanobiotechnology Major, Seoul National University, Seoul 110-749, Korea.
Abstract
- Huntington's disease is caused by CAG trinucleotide expansions in the gene encoding huntingtin. N- terminal fragments of huntingtin with polyglutamine produce aggregates in the endosome-lysosomal system, where proteolytic fragments of huntingtin is generated. Heat shock protein 70 (HSP70) prevents the formation of protein aggregates, but the effect of HSP70 on the huntingtin in the endosome-lysosomal system is unknown. This study was to determine whether HSP70 alters the distribution of huntingtin in endosome-lysosomal system. HSP70 expressing stable cells (NIH/3T3 or cerebral hybrid cell line A1) were generated, and mutant [(CAG)100] huntingtin was transiently overexpressed. Analysis of subcellular distribution by immnuocytochemistry or proteolysis cleavage by Western blotting was performed. 18 CAG repeat wild type [WT; (CAG)18] huntingtin was used as a control. Cells with huntingtin showed patterns of endosome- lysosomal accumulation, from a 'dispersed vacuole (DV)' type into a coalescent 'perinuclear vacuole (PV)' type over time. In WT huntingtin, HSP70 increased the cells with the PV types that enhanced the proteolytic cleavage of huntingtin. However, HSP70 reduced cells of the DV and PV types expressing mutant huntingtin, that result in less proteolysis than that of control. In addition, intranuclear inclusions were formed only in mutant cells, which was not affected by HSP70. These results suggest that HSP70 alters the distribution of huntingtin in the endosome-lysosomal system, and that this contributes to huntingtin proteolysis.
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