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

J. Biol. Chem., Vol. 280, Issue 24, 22809-22818, June 17, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/24/22809    most recent M500390200v2 M500390200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gokhale, K. C. Articles by Chernoff, Y. O. Search for Related Content PubMed PubMed Citation Articles by Gokhale, K. C. Articles by Chernoff, Y. O. Social Bookmarking                      What's this?

Modulation of Prion-dependent Polyglutamine Aggregation and Toxicity by Chaperone Proteins in the Yeast Model^*

Kavita C. Gokhale, Gary P. Newnam, Michael Y. Sherman, and Yury O. Chernoff¶

From the School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332 and the Department of Biochemistry, Boston University Medical School, Boston, Massachusetts 02118

In yeast, aggregation and toxicity of the expanded polyglutamine fragment of human huntingtin strictly depend on the presence of the endogenous self-perpetuating aggregated proteins (prions), which contain glutamine/asparagine-rich domains. Some chaperones of the Hsp100/70/40 complex, modulating propagation of yeast prions, were also reported to influence polyglutamine aggregation in yeast, but it was not clear whether they do it directly or via affecting prions. Our data show that although some chaperone alterations indeed act on polyglutamines via curing endogenous prions, other alterations decrease size and ameliorate toxicity of polyglutamine aggregates without affecting prion propagation. Therefore, the role of yeast chaperones in polyglutamine aggregation and toxicity is not restricted only to their effects on the endogenous prions. Moreover, chaperone interactions with prion and polyglutamine aggregates appear to be of a highly specific nature. One and the same chaperone alteration, substitution A503V in the middle region of the chaperone Hsp104, exhibited opposite effects on one of the endogenous prions ([PSI⁺], the prion form of Sup35) and on polyglutamines, increasing aggregate size and toxicity in the former case and decreasing them in the latter case. On the other hand, different members of a single chaperone family exhibited opposite effects on one and the same type of aggregates: excess of the Hsp40 chaperone Ydj1 increased polyglutamine aggregate size and toxicity, whereas excess of the other Hsp40 chaperone, Sis1, decreased them. As many stress-defense proteins are conserved between yeast and mammals, these data shed light on possible mechanisms modulating polyglutamine aggregation and toxicity in mammalian cells.

Received for publication, January 12, 2005 , and in revised form, April 6, 2005.

^* This work was supported by grants from The Huntington's Disease Society of America and from the National Institutes of Health (Grant R01GM58763) (to Y. O. C.). 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: School of Biology, Georgia Institute of Technology, 310 Ferst Dr., Atlanta, GA 30332-0230. Tel.: 404-894-1157; Fax: 404-894-0519; E-mail: yury.chernoff{at}biology.gatech.edu.

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

This article has been cited by other articles:

				L.-B. Li, K. Xu, and N. M. Bonini Suppression of Polyglutamine Toxicity by the Yeast Sup35 Prion Domain in Drosophila J. Biol. Chem., December 28, 2007; 282(52): 37694 - 37701. [Abstract] [Full Text] [PDF]

				A. B. Meriin, X. Zhang, I. M. Alexandrov, A. B. Salnikova, M. D. Ter-Avanesian, Y. O. Chernoff, and M. Y. Sherman Endocytosis machinery is involved in aggregation of proteins with expanded polyglutamine domains FASEB J, June 1, 2007; 21(8): 1915 - 1925. [Abstract] [Full Text] [PDF]

				H.-Y. Lian, H. Zhang, Z.-R. Zhang, H. M. Loovers, G. W. Jones, P. J. E. Rowling, L. S. Itzhaki, J.-M. Zhou, and S. Perrett Hsp40 Interacts Directly with the Native State of the Yeast Prion Protein Ure2 and Inhibits Formation of Amyloid-like Fibrils J. Biol. Chem., April 20, 2007; 282(16): 11931 - 11940. [Abstract] [Full Text] [PDF]

				K. D. Allen, T. A. Chernova, E. P. Tennant, K. D. Wilkinson, and Y. O. Chernoff Effects of Ubiquitin System Alterations on the Formation and Loss of a Yeast Prion J. Biol. Chem., February 2, 2007; 282(5): 3004 - 3013. [Abstract] [Full Text] [PDF]

				H. M. Loovers, E. Guinan, and G. W. Jones Importance of the Hsp70 ATPase Domain in Yeast Prion Propagation Genetics, February 1, 2007; 175(2): 621 - 630. [Abstract] [Full Text] [PDF]

				B. Dehay and A. Bertolotti Critical Role of the Proline-rich Region in Huntingtin for Aggregation and Cytotoxicity in Yeast J. Biol. Chem., November 24, 2006; 281(47): 35608 - 35615. [Abstract] [Full Text] [PDF]

				K.-W. Park, J.-S. Hahn, Q. Fan, D. J. Thiele, and L. Li De Novo Appearance and "Strain" Formation of Yeast Prion [PSI+] Are Regulated by the Heat-Shock Transcription Factor Genetics, May 1, 2006; 173(1): 35 - 47. [Abstract] [Full Text] [PDF]

				H. Wang, P. J. Lim, C. Yin, M. Rieckher, B. E. Vogel, and M. J. Monteiro Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin Hum. Mol. Genet., March 15, 2006; 15(6): 1025 - 1041. [Abstract] [Full Text] [PDF]

				E. E. Ganusova, L. N. Ozolins, S. Bhagat, G. P. Newnam, R. D. Wegrzyn, M. Y. Sherman, and Y. O. Chernoff Modulation of Prion Formation, Aggregation, and Toxicity by the Actin Cytoskeleton in Yeast Mol. Cell. Biol., January 15, 2006; 26(2): 617 - 629. [Abstract] [Full Text] [PDF]