HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 27, 25143-25150, July 4, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/27/25143    most recent M302975200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ishihara, K. Articles by Hatayama, T. Search for Related Content PubMed PubMed Citation Articles by Ishihara, K. Articles by Hatayama, T. Social Bookmarking                      What's this?

Hsp105 Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity^*

Keiichi Ishihara , Nobuyuki Yamagishi , Youhei Saito , Hiroaki Adachi , Yasushi Kobayashi , Gen Sobue , Kenzo Ohtsuka ¶ and Takumi Hatayama  ||

From the Department of Biochemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, the Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya 466-8550, and the ^¶Department of Environmental Biology, College of Bioscience and Biotechnology, Chubu University, Matsumoto-cho 1200, Kasugai 487-8501, Japan

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The N-terminal fragment of AR containing the expanded polyglutamine tract aggregates in cytoplasm and/or in nucleus and induces cell death. Some chaperones such as Hsp40 and Hsp70 have been identified as important regulators of polyglutamine aggregation and/or cell death in neuronal cells. Recently, Hsp105, expressed at especially high levels in mammalian brain, has been shown to suppress apoptosis in neuronal cells and prevent the aggregation of protein caused by heat shock in vitro. However, its role in polyglutamine-mediated cell death and toxicity has not been studied. In the present study, we examined the effects of Hsp105 on the aggregation and cell toxicity caused by expansion of the polyglutamine tract using a cellular model of SBMA. The transient expression of truncated ARs (tARs) containing an expanded polyglutamine tract caused aggregates to form in COS-7 and SK-N-SH cells and concomitantly apoptosis in the cells with the nuclear aggregates. When Hsp105 was overexpressed with tAR97 in the cells, Hsp105 was colocalized to aggregates of tAR97, and the aggregation and cell toxicity caused by expansion of the polyglutamine tract were markedly reduced. Both -sheet and -helix domains, but not the ATPase domain, of Hsp105 were necessary to suppress the formation of aggregates in vivo and in vitro. Furthermore, Hsp105 was found to localize in nuclear inclusions formed by ARs containing an expanded polyglutamine tract in tissues of patients and transgenic mice with SBMA. These findings suggest that overexpression of Hsp105 suppresses cell death caused by expansion of the polyglutamine tract without chaperone activity, and the enhanced expression of the essential domains of Hsp105 in brain may provide an effective therapeutic approach for CAG repeat diseases.

Received for publication, March 24, 2003 , and in revised form, April 21, 2003.

^* This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Culture, and Sports of Japan (to T. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Fax: 81-75-595-4758; E-mail: hatayama{at}mb.kyoto-phu.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. L. Montie, M. S. Cho, L. Holder, Y. Liu, A. S. Tsvetkov, S. Finkbeiner, and D. E. Merry Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy Hum. Mol. Genet., June 1, 2009; 18(11): 1937 - 1950. [Abstract] [Full Text] [PDF]

				Y. Saito, N. Yamagishi, and T. Hatayama Nuclear Localization Mechanism of Hsp105{beta} and its Possible Function in Mammalian Cells J. Biochem., February 1, 2009; 145(2): 185 - 191. [Abstract] [Full Text] [PDF]

				N. Fujikake, Y. Nagai, H. A. Popiel, Y. Okamoto, M. Yamaguchi, and T. Toda Heat Shock Transcription Factor 1-activating Compounds Suppress Polyglutamine-induced Neurodegeneration through Induction of Multiple Molecular Chaperones J. Biol. Chem., September 19, 2008; 283(38): 26188 - 26197. [Abstract] [Full Text] [PDF]

				L. Shaner, H. Wegele, J. Buchner, and K. A. Morano The Yeast Hsp110 Sse1 Functionally Interacts with the Hsp70 Chaperones Ssa and Ssb J. Biol. Chem., December 16, 2005; 280(50): 41262 - 41269. [Abstract] [Full Text] [PDF]

				M. Katsuno, C. Sang, H. Adachi, M. Minamiyama, M. Waza, F. Tanaka, M. Doyu, and G. Sobue Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease PNAS, November 15, 2005; 102(46): 16801 - 16806. [Abstract] [Full Text] [PDF]

				M. Fujimoto, E. Takaki, T. Hayashi, Y. Kitaura, Y. Tanaka, S. Inouye, and A. Nakai Active HSF1 Significantly Suppresses Polyglutamine Aggregate Formation in Cellular and Mouse Models J. Biol. Chem., October 14, 2005; 280(41): 34908 - 34916. [Abstract] [Full Text] [PDF]

				D. Helmlinger, J. Bonnet, J.-L. Mandel, Y. Trottier, and D. Devys Hsp70 and Hsp40 Chaperones Do Not Modulate Retinal Phenotype in SCA7 Mice J. Biol. Chem., December 31, 2004; 279(53): 55969 - 55977. [Abstract] [Full Text] [PDF]

				D. G. Hay, K. Sathasivam, S. Tobaben, B. Stahl, M. Marber, R. Mestril, A. Mahal, D. L. Smith, B. Woodman, and G. P. Bates Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach Hum. Mol. Genet., July 1, 2004; 13(13): 1389 - 1405. [Abstract] [Full Text] [PDF]

				L. Shaner, A. Trott, J. L. Goeckeler, J. L. Brodsky, and K. A. Morano The Function of the Yeast Molecular Chaperone Sse1 Is Mechanistically Distinct from the Closely Related Hsp70 Family J. Biol. Chem., May 21, 2004; 279(21): 21992 - 22001. [Abstract] [Full Text] [PDF]