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

J. Biol. Chem., Vol. 279, Issue 19, 20211-20220, May 7, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/19/20211    most recent M401267200v1 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 Gafni, J. Articles by Ellerby, L. M. Search for Related Content PubMed PubMed Citation Articles by Gafni, J. Articles by Ellerby, L. M. Social Bookmarking                      What's this?

Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity

ACCUMULATION OF CALPAIN/CASPASE FRAGMENTS IN THE NUCLEUS^*

Juliette Gafni, Evan Hermel¶, Jessica E. Young, Cheryl L. Wellington||, Michael R. Hayden**, and Lisa M. Ellerby

From the The Buck Institute for Age Research, Novato, California 94945, the ^¶Touro University College of Osteopathic Medicine, Vallejo, California 94592, and the ^||Department of Pathology and Laboratory Medicine and the ^**Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) tract expansion near the N terminus of huntingtin (Htt). Proteolytic processing of mutant Htt and abnormal calcium signaling may play a critical role in disease progression and pathogenesis. Recent work indicates that calpains may participate in the increased and/or altered patterns of Htt proteolysis leading to the selective toxicity observed in HD striatum. Here, we identify two calpain cleavage sites in Htt and show that mutation of these sites renders the polyQ expanded Htt less susceptible to proteolysis and aggregation, resulting in decreased toxicity in an in vitro cell culture model. In addition, we found that calpain- and caspase-derived Htt fragments preferentially accumulate in the nucleus without the requirement of further cleavage into smaller fragments. Calpain family members, calpain-1, -5, -7, and -10, have increased levels or are activated in HD tissue culture and transgenic mouse models, suggesting they may play a key role in Htt proteolysis and disease pathology. Interestingly, calpain-1, -5, -7, and -10 localize to the cytoplasm and the nucleus, whereas the activated forms of calpain-7 and -10 are found only in the nucleus. These results support the role of calpain-derived Htt fragmentation in HD and suggest that aberrant activation of calpains may play a role in HD pathogenesis.

Received for publication, February 4, 2004

^* This work was supported in part by the Hereditary Disease Foundation (to L. M. E., C. L. W., and M. R. H.) and the Huntington's Disease Society of America (to M. R. H. and L. M. E.). 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.

Supported by a National Institutes of Health (NIH) postdoctoral fellowship F32 NS043937.

Holds a Canada Research Chair in human genetics (MT9133) and has additional funding from the Canadian Institutes of Health Research and the Canadian Genetic Diseases Network.

Supported by NIH Grant NS40251A and the Muscular Dystrophy Association. To whom correspondence should be addressed: Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945. Tel.: 415-209-2088; Fax: 415-209-2230; E-mail: lellerby{at}buckinstitute.org.

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

This article has been cited by other articles:

				S. C. Warby, C. N. Doty, R. K. Graham, J. B. Carroll, Y.-Z. Yang, R. R. Singaraja, C. M. Overall, and M. R. Hayden Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus Hum. Mol. Genet., August 1, 2008; 17(15): 2390 - 2404. [Abstract] [Full Text] [PDF]

				J. Liu, M. C. Liu, and K. K. W. Wang Calpain in the CNS: From Synaptic Function to Neurotoxicity Sci. Signal., April 8, 2008; 1(14): re1 - re1. [Abstract] [Full Text] [PDF]

				J. E. Young, L. Gouw, S. Propp, B. L. Sopher, J. Taylor, A. Lin, E. Hermel, A. Logvinova, S. F. Chen, S. Chen, et al. Proteolytic Cleavage of Ataxin-7 by Caspase-7 Modulates Cellular Toxicity and Transcriptional Dysregulation J. Biol. Chem., October 12, 2007; 282(41): 30150 - 30160. [Abstract] [Full Text] [PDF]

				A. Haacke, F. U. Hartl, and P. Breuer Calpain Inhibition Is Sufficient to Suppress Aggregation of Polyglutamine-expanded Ataxin-3 J. Biol. Chem., June 29, 2007; 282(26): 18851 - 18856. [Abstract] [Full Text] [PDF]

				H. Fukui and C. T. Moraes Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates Hum. Mol. Genet., April 1, 2007; 16(7): 783 - 797. [Abstract] [Full Text] [PDF]

				M. Bartoli, N. Bourg, D. Stockholm, F. Raynaud, A. Delevacque, Y. Han, P. Borel, K. Seddik, N. Armande, and I. Richard A Mouse Model for Monitoring Calpain Activity under Physiological and Pathological Conditions J. Biol. Chem., December 22, 2006; 281(51): 39672 - 39680. [Abstract] [Full Text] [PDF]

				Y. Yajima, M. Sato, H. Sorimachi, M. Inomata, M. Maki, and S. Kawashima Calpain System Regulates the Differentiation of Adult Primitive Mesenchymal ST-13 Adipocytes Endocrinology, October 1, 2006; 147(10): 4811 - 4819. [Abstract] [Full Text] [PDF]

				B. Schilling, J. Gafni, C. Torcassi, X. Cong, R. H. Row, M. A. LaFevre-Bernt, M. P. Cusack, T. Ratovitski, R. Hirschhorn, C. A. Ross, et al. Huntingtin Phosphorylation Sites Mapped by Mass Spectrometry: MODULATION OF CLEAVAGE AND TOXICITY J. Biol. Chem., August 18, 2006; 281(33): 23686 - 23697. [Abstract] [Full Text] [PDF]

				W. Li, L. C. Serpell, W. J. Carter, D. C. Rubinsztein, and J. A. Huntington Expression and Characterization of Full-length Human Huntingtin, an Elongated HEAT Repeat Protein J. Biol. Chem., June 9, 2006; 281(23): 15916 - 15922. [Abstract] [Full Text] [PDF]

				S. J. Franco and A. Huttenlocher Regulating cell migration: calpains make the cut J. Cell Sci., September 1, 2005; 118(17): 3829 - 3838. [Abstract] [Full Text] [PDF]

				T. Nguyen, A. Hamby, and S. M. Massa Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model PNAS, August 16, 2005; 102(33): 11840 - 11845. [Abstract] [Full Text] [PDF]

				H. Rangone, R. Pardo, E. Colin, J.-A. Girault, F. Saudou, and S. Humbert Phosphorylation of Arfaptin 2 at Ser260 by Akt Inhibits PolyQ-huntingtin-induced Toxicity by Rescuing Proteasome Impairment J. Biol. Chem., June 10, 2005; 280(23): 22021 - 22028. [Abstract] [Full Text] [PDF]

				M. A. Poirier, H. Jiang, and C. A. Ross A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure Hum. Mol. Genet., March 15, 2005; 14(6): 765 - 774. [Abstract] [Full Text] [PDF]

				B. Tremper-Wells and M. L. Vallano Nuclear Calpain Regulates Ca2+-dependent Signaling via Proteolysis of Nuclear Ca2+/Calmodulin-dependent Protein Kinase Type IV in Cultured Neurons J. Biol. Chem., January 21, 2005; 280(3): 2165 - 2175. [Abstract] [Full Text] [PDF]

				D. Goti, S. M. Katzen, J. Mez, N. Kurtis, J. Kiluk, L. Ben-Haiem, N. A. Jenkins, N. G. Copeland, A. Kakizuka, A. H. Sharp, et al. A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration J. Neurosci., November 10, 2004; 24(45): 10266 - 10279. [Abstract] [Full Text] [PDF]