Small Changes, Big Impact: Posttranslational Modifications and Function of Huntingtin in Huntington Disease

Overview

Journal Neuroscientist

Publisher Sage Publications

Specialty Neurology

Date 2011 Feb 12

PMID 21311053

Citations 82

Authors

Dagmar E Ehrnhoefer

Liza Sutton

Michael R Hayden

Affiliations

Soon will be listed here.

Abstract

Huntington disease (HD) is a neurodegenerative disorder caused by an elongated polyglutamine tract in huntingtin (htt). htt normally undergoes different posttranslational modifications (PTMs), including phosphorylation, SUMOylation, ubiquitination, acetylation, proteolytic cleavage, and palmitoylation. In the presence of the HD mutation, some PTMs are significantly altered and can result in changes in the clinical phenotype. A rate-limiting PTM is defined as one that can result in significant effects on the phenotype in animal models. For example, the prevention of proteolysis at D586 as well as constitutive phosphorylation at S13 and S16 can obviate the expression of phenotypic features of HD. The enzymes involved in these modifications such as caspase-6, the IκB kinase (IKK) complex, and still to be characterized phosphatases therefore represent promising therapeutic targets for HD. Identifying and testing specific modulators of PTMs now constitute the next big challenges in order to further validate these targets and proceed towards the goal of a mechanism-based treatment for HD.

Citing Articles

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References

Preisinger E, JORDAN B, Kazantsev A, Housman D . Evidence for a recruitment and sequestration mechanism in Huntington's disease. Philos Trans R Soc Lond B Biol Sci. 1999; 354(1386):1029-34. PMC: 1692605. DOI: 10.1098/rstb.1999.0455. View

Hockly E, Richon V, Woodman B, Smith D, Zhou X, Rosa E . Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003; 100(4):2041-6. PMC: 149955. DOI: 10.1073/pnas.0437870100. View

Landry Y, Gies J . Drugs and their molecular targets: an updated overview. Fundam Clin Pharmacol. 2008; 22(1):1-18. DOI: 10.1111/j.1472-8206.2007.00548.x. View

Chan H, Warrick J, Andriola I, Merry D, Bonini N . Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet. 2002; 11(23):2895-904. DOI: 10.1093/hmg/11.23.2895. View

Tan J, Song J, Chen Y, Durrin L . Phosphorylation-dependent interaction of SATB1 and PIAS1 directs SUMO-regulated caspase cleavage of SATB1. Mol Cell Biol. 2010; 30(11):2823-36. PMC: 2876529. DOI: 10.1128/MCB.01603-09. View

Bessert D, Gutridge K, DUNBAR J, Carlock L . The identification of a functional nuclear localization signal in the Huntington disease protein. Brain Res Mol Brain Res. 1995; 33(1):165-73. DOI: 10.1016/0169-328x(95)00124-b. View

Ellerby L, Andrusiak R, Wellington C, Hackam A, Propp S, Wood J . Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. J Biol Chem. 1999; 274(13):8730-6. DOI: 10.1074/jbc.274.13.8730. View

Zala D, Colin E, Rangone H, Liot G, Humbert S, Saudou F . Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet. 2008; 17(24):3837-46. DOI: 10.1093/hmg/ddn281. View

Kim M, Lee H, Laforet G, McIntyre C, Martin E, Chang P . Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci. 1999; 19(3):964-73. PMC: 6782141. View

10.

Drisdel R, Manzana E, Green W . The role of palmitoylation in functional expression of nicotinic alpha7 receptors. J Neurosci. 2004; 24(46):10502-10. PMC: 6730317. DOI: 10.1523/JNEUROSCI.3315-04.2004. View

11.

Terashima T, Kawai H, Fujitani M, Maeda K, Yasuda H . SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death. Neuroreport. 2002; 13(17):2359-64. DOI: 10.1097/00001756-200212030-00038. View

12.

Toneff T, Hwang S, Chesselet M, Hook V . 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. J Neurosci. 2001; 21(6):1830-7. PMC: 6762596. View

13.

Zhang Y, Li M, Drozda M, Chen M, Ren S, Mejia Sanchez R . Depletion of wild-type huntingtin in mouse models of neurologic diseases. J Neurochem. 2003; 87(1):101-6. DOI: 10.1046/j.1471-4159.2003.01980.x. View

14.

Saudou F, Finkbeiner S, Devys D, Greenberg M . Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998; 95(1):55-66. DOI: 10.1016/s0092-8674(00)81782-1. View

15.

Li W, Serpell L, Carter W, Rubinsztein D, Huntington J . Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein. J Biol Chem. 2006; 281(23):15916-22. DOI: 10.1074/jbc.M511007200. View

16.

Mahrus S, Trinidad J, Barkan D, Sali A, Burlingame A, Wells J . Global sequencing of proteolytic cleavage sites in apoptosis by specific labeling of protein N termini. Cell. 2008; 134(5):866-76. PMC: 2566540. DOI: 10.1016/j.cell.2008.08.012. View

17.

Goldberg Y, Nicholson D, Rasper D, Kalchman M, Koide H, Graham R . Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet. 1996; 13(4):442-9. DOI: 10.1038/ng0896-442. View

18.

Warby S, Chan E, Metzler M, Gan L, Singaraja R, Crocker S . Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum Mol Genet. 2005; 14(11):1569-77. DOI: 10.1093/hmg/ddi165. View

19.

Gafni J, Hermel E, Young J, Wellington C, Hayden M, Ellerby L . Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. J Biol Chem. 2004; 279(19):20211-20. DOI: 10.1074/jbc.M401267200. View

20.

Graham R, Deng Y, Carroll J, Vaid K, Cowan C, Pouladi M . Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci. 2010; 30(45):15019-29. PMC: 3074336. DOI: 10.1523/JNEUROSCI.2071-10.2010. View