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The Journal of Neuroscience, January 24, 2007, 27(4):868-880; doi:10.1523/JNEUROSCI.4522-06.2007

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Neurobiology of Disease
The Induction Levels of Heat Shock Protein 70 Differentiate the Vulnerabilities to Mutant Huntingtin among Neuronal Subtypes

Kazuhiko Tagawa,¹ Shigeki Marubuchi,^1,2 Mei-Ling Qi,^1,3 Yasushi Enokido,¹ Takuya Tamura,¹ Reina Inagaki,¹ Miho Murata,³ Ichiro Kanazawa,⁴ Erich E. Wanker,⁵ and Hitoshi Okazawa^1,3

¹Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, ²Toyama Chemical Company, Toyama 930-8508, Japan, ³PRESTO, Japan Science and Technology Agency, Kawagoe 332-0012, Japan, ⁴National Center for Neurology and Psychiatry, Kodaira 187-8502, Japan, and ⁵Max-Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany

Correspondence should be addressed to Hitoshi Okazawa, Department of Neuropathology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Email: okazawa-tky{at}umin.ac.jp

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 ) 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.

Key words: polyglutamine; transcriptome; hsp70; huntingtin; cell death; microarray

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Received Aug. 13, 2006; revised Dec. 9, 2006; accepted Dec. 10, 2006.

Correspondence should be addressed to Hitoshi Okazawa, Department of Neuropathology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Email: okazawa-tky{at}umin.ac.jp

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