QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter 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 Web of Science 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 Web of Science (60) Citing Articles via Google Scholar Google Scholar Articles by Mende-Mueller, L. M. Articles by Hook, V. Y. H. Search for Related Content PubMed PubMed Citation Articles by Mende-Mueller, L. M. Articles by Hook, V. Y. H.

 Previous Article  |  Next Article 

The Journal of Neuroscience, March 15, 2001, 21(6):1830-1837

Tissue-Specific Proteolysis of Huntingtin (htt) in Human Brain: Evidence of Enhanced Levels of N- and C-Terminal htt Fragments in Huntington's Disease Striatum

Liane M. Mende-Mueller¹, Thomas Toneff^{1, 2}, Shin-Rong Hwang^{1, 2}, Marie-Francoise Chesselet³, and Vivian Y. H. Hook^{1, 2}

¹ Departments of Medicine and Neuroscience, University of California, San Diego, San Diego, California 92093, ² Buck Institute for Age Research, Novato, California 94945, and ³ Department of Neurology, University of California, Los Angeles, Los Angeles, California 90095

Proteolysis of mutant huntingtin (htt) has been hypothesized to occur in Huntington's disease (HD) brains. Therefore, this in vivo study examined htt fragments in cortex and striatum of adult HD and control human brains by Western blots, using domain-specific anti-htt antibodies that recognize N- and C-terminal domains of htt (residues 181-810 and 2146-2541, respectively), as well as the 17 residues at the N terminus of htt. On the basis of the patterns of htt fragments observed, different "protease-susceptible domains" were identified for proteolysis of htt in cortex compared with striatum, suggesting that htt undergoes tissue-specific proteolysis. In cortex, htt proteolysis occurs within two different N-terminal domains, termed protease-susceptible domains "A" and "B." However, in striatum, a different pattern of fragments indicated that proteolysis of striatal htt occurred within a C-terminal domain termed "C," as well as within the N-terminal domain region designated "A". Importantly, striatum from HD brains showed elevated levels of 40-50 kDa N-terminal and 30-50 kDa C-terminal fragments compared with that of controls. Increased levels of these htt fragments may occur from a combination of enhanced production or retarded degradation of fragments. Results also demonstrated tissue-specific ubiquitination of certain htt N-terminal fragments in striatum compared with cortex. Moreover, expansions of the triplet-repeat domain of the IT15 gene encoding htt was confirmed for the HD tissue samples studied. Thus, regulated tissue-specific proteolysis and ubiquitination of htt occur in human HD brains. These results suggest that the role of huntingtin proteolysis should be explored in the pathogenic mechanisms of HD.

Key words: Huntington's disease; huntingtin; proteolytic fragments; brain; neurodegenerative disease; ubiquitin

---

Copyright © 2001 Society for Neuroscience  0270-6474/01/2161830-08$05.00/0

This article has been cited by other articles:

				T. Ratovitski, M. Gucek, H. Jiang, E. Chighladze, E. Waldron, J. D'Ambola, Z. Hou, Y. Liang, M. A. Poirier, R. R. Hirschhorn, et al. Mutant Huntingtin N-terminal Fragments of Specific Size Mediate Aggregation and Toxicity in Neuronal Cells J. Biol. Chem., April 17, 2009; 284(16): 10855 - 10867. [Abstract] [Full Text] [PDF]

				M. L. Duennwald, S. Jagadish, P. J. Muchowski, and S. Lindquist Flanking sequences profoundly alter polyglutamine toxicity in yeast PNAS, July 18, 2006; 103(29): 11045 - 11050. [Abstract] [Full Text] [PDF]

				R. Pardo, E. Colin, E. Regulier, P. Aebischer, N. Deglon, S. Humbert, and F. Saudou Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421 J. Neurosci., February 1, 2006; 26(5): 1635 - 1645. [Abstract] [Full Text] [PDF]

				S. C. Warby, E. Y. Chan, M. Metzler, L. Gan, R. R. Singaraja, S. F. Crocker, H. A. Robertson, and M. R. Hayden Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo Hum. Mol. Genet., June 1, 2005; 14(11): 1569 - 1577. [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]

				G. M. Zainelli, C. A. Ross, J. C. Troncoso, J. K. Fitzgerald, and N. A. Muma Calmodulin Regulates Transglutaminase 2 Cross-Linking of Huntingtin J. Neurosci., February 25, 2004; 24(8): 1954 - 1961. [Abstract] [Full Text] [PDF]

				Z.-H. Qin, Y. Wang, K. B. Kegel, A. Kazantsev, B. L. Apostol, L. M. Thompson, J. Yoder, N. Aronin, and M. DiFiglia Autophagy regulates the processing of amino terminal huntingtin fragments Hum. Mol. Genet., December 15, 2003; 12(24): 3231 - 3244. [Abstract] [Full Text] [PDF]

				H. Zhou, F. Cao, Z. Wang, Z.-X. Yu, H.-P. Nguyen, J. Evans, S.-H. Li, and X.-J. Li Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity J. Cell Biol., October 13, 2003; 163(1): 109 - 118. [Abstract] [Full Text] [PDF]

				J. Xia, D. H. Lee, J. Taylor, M. Vandelft, and R. Truant Huntingtin contains a highly conserved nuclear export signal Hum. Mol. Genet., June 15, 2003; 12(12): 1393 - 1403. [Abstract] [Full Text] [PDF]

				F. C. Nucifora Jr., L. M. Ellerby, C. L. Wellington, J. D. Wood, W. J. Herring, A. Sawa, M. R. Hayden, V. L. Dawson, T. M. Dawson, and C. A. Ross Nuclear Localization of a Non-caspase Truncation Product of Atrophin-1, with an Expanded Polyglutamine Repeat, Increases Cellular Toxicity J. Biol. Chem., April 4, 2003; 278(15): 13047 - 13055. [Abstract] [Full Text] [PDF]

				Z.-X. Yu, S.-H. Li, J. Evans, A. Pillarisetti, H. Li, and X.-J. Li Mutant Huntingtin Causes Context-Dependent Neurodegeneration in Mice with Huntington's Disease J. Neurosci., March 15, 2003; 23(6): 2193 - 2202. [Abstract] [Full Text] [PDF]

				J. L. Walcott and D. E. Merry Ligand Promotes Intranuclear Inclusions in a Novel Cell Model of Spinal and Bulbar Muscular Atrophy J. Biol. Chem., December 20, 2002; 277(52): 50855 - 50859. [Abstract] [Full Text] [PDF]

				D. Goffredo, D. Rigamonti, M. Tartari, A. De Micheli, C. Verderio, M. Matteoli, C. Zuccato, and E. Cattaneo Calcium-dependent Cleavage of Endogenous Wild-type Huntingtin in Primary Cortical Neurons J. Biol. Chem., October 11, 2002; 277(42): 39594 - 39598. [Abstract] [Full Text] [PDF]

				C. L. Wellington, L. M. Ellerby, C.-A. Gutekunst, D. Rogers, S. Warby, R. K. Graham, O. Loubser, J. van Raamsdonk, R. Singaraja, Y.-Z. Yang, et al. Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease J. Neurosci., September 15, 2002; 22(18): 7862 - 7872. [Abstract] [Full Text] [PDF]

				R. Luthi-Carter, S. A. Hanson, A. D. Strand, D. A. Bergstrom, W. Chun, N. L. Peters, A. M. Woods, E. Y. Chan, C. Kooperberg, D. Krainc, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain Hum. Mol. Genet., August 15, 2002; 11(17): 1911 - 1926. [Abstract] [Full Text] [PDF]

				E. Y.W. Chan, R. Luthi-Carter, A. Strand, S. M. Solano, S. A. Hanson, M. M. DeJohn, C. Kooperberg, K. O. Chase, M. DiFiglia, A. B. Young, et al. Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease Hum. Mol. Genet., August 15, 2002; 11(17): 1939 - 1951. [Abstract] [Full Text] [PDF]

				A. W. Dunah, H. Jeong, A. Griffin, Y.-M. Kim, D. G. Standaert, S. M. Hersch, M. M. Mouradian, A. B. Young, N. Tanese, and D. Krainc Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease Science, June 21, 2002; 296(5576): 2238 - 2243. [Abstract] [Full Text] [PDF]

				K. B. Kegel, A. R. Meloni, Y. Yi, Y. J. Kim, E. Doyle, B. G. Cuiffo, E. Sapp, Y. Wang, Z.-H. Qin, J. D. Chen, et al. Huntingtin Is Present in the Nucleus, Interacts with the Transcriptional Corepressor C-terminal Binding Protein, and Represses Transcription J. Biol. Chem., February 22, 2002; 277(9): 7466 - 7476. [Abstract] [Full Text] [PDF]

				A. Khoshnan, J. Ko, and P. H. Patterson Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity PNAS, January 22, 2002; 99(2): 1002 - 1007. [Abstract] [Full Text] [PDF]

				R. O. S. Mejia and R. M. Friedlander Caspases in Huntington's Disease Neuroscientist, December 1, 2001; 7(6): 480 - 489. [Abstract] [PDF]

				S Davies and D B Ramsden Huntington's disease Mol. Pathol., December 1, 2001; 54(6): 409 - 413. [Abstract] [Full Text] [PDF]

				Y. J. Kim, Y. Yi, E. Sapp, Y. Wang, B. Cuiffo, K. B. Kegel, Z.-H. Qin, N. Aronin, and M. DiFiglia Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis PNAS, October 23, 2001; 98(22): 12784 - 12789. [Abstract] [Full Text] [PDF]

				A. Khoshnan, J. Ko, and P. H. Patterson Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity PNAS, January 22, 2002; 99(2): 1002 - 1007. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help