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The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes

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Item Type:Article
Title:The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes
Creators Name:Tagawa, K. and Marubuchi, S. and Qi, M.L. and Enokido, Y. and Tamura, T. and Inagaki, R. and Murata, M. and Kanazawa, I. and Wanker, E.E. and Okazawa, H.
Abstract:The reason why vulnerabilities to mutant polyglutamine (polyQ) proteins are different among neuronal subtypes is mostly unknown. In this study, we compared the gene expression profiles of three types of primary neurons expressing huntingtin (htt) or ataxin-1. We found that heat shock protein 70 (hsp70), a well known chaperone molecule protecting neurons in the polyQ pathology, was dramatically upregulated only by mutant htt and selectively in the granule cells of the cerebellum. Granule cells, which are insensitive to degeneration in the human Huntington's disease (HD) pathology, lost their resistance by suppressing hsp70 with siRNA, whereas cortical neurons, affected in human HD, gained resistance by overexpressing hsp70. This indicates that induction levels of hsp70 are a critical factor for determining vulnerabilities to mutant htt among neuronal subtypes. CAT (chloramphenicol acetyltransferase) assays showed that CBF (CCAAT box binding factor, CCAAT/enhancer binding protein zeta) activated, but p53 repressed transcription of the hsp70 gene in granule cells. Basal and mutant htt-induced expression levels of p53 were remarkably lower in granule cells than in cortical neurons, suggesting that different magnitudes of p53 are linked to distinct induction levels of hsp70. Surprisingly, however, heat shock factor 1 was not activated in granule cells by mutant htt. Collectively, different levels of hsp70 among neuronal subtypes might be involved in selective neuronal death in the HD pathology.
Keywords:Polyglutamine, Transcriptome, hsp70, Huntingtin, Cell Death, Microarray
Source:Journal of Neuroscience
Publisher:Society for Neuroscience
Page Range:868-880
Date:24 January 2007
Additional Information:Copyright (c) 2007 by The Society for Neuroscience
Official Publication:https://doi.org/10.1523/JNEUROSCI.4522-06.2007
PubMed:View item in PubMed

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