| Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. | |
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MedLine Citation:
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PMID: 21068307 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Caspase cleavage of huntingtin (htt) and nuclear htt accumulation represent early neuropathological changes in brains of patients with Huntington's disease (HD). However, the relationship between caspase cleavage of htt and caspase activation patterns in the pathogenesis of HD remains poorly understood. The lack of a phenotype in YAC mice expressing caspase-6-resistant (C6R) mutant htt (mhtt) highlights proteolysis of htt at the 586 aa caspase-6 (casp6) site as a key mechanism in the pathology of HD. The goal of this study was to investigate how proteolysis of htt at residue 586 plays a role in the pathogenesis of HD and determine whether inhibiting casp6 cleavage of mhtt alters cell-death pathways in vivo. Here we demonstrate that activation of casp6, and not caspase-3, is observed before onset of motor abnormalities in human and murine HD brain. Active casp6 levels correlate directly with CAG size and inversely with age of onset. In contrast, in vivo expression of C6R mhtt attenuates caspase activation. Increased casp6 activity and apoptotic cell death is evident in primary striatal neurons expressing caspase-cleavable, but not C6R, mhtt after NMDA application. Pretreatment with a casp6 inhibitor rescues the apoptotic cell death observed in this paradigm. These data demonstrate that activation of casp6 is an early marker of disease in HD. Furthermore, these data provide a clear link between excitotoxic pathways and proteolysis and suggest that C6R mhtt protects against neurodegeneration by influencing the activation of neuronal cell-death and excitotoxic pathways operative in HD. |
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Authors:
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Rona K Graham; Yu Deng; Jeffery Carroll; Kuljeet Vaid; Catherine Cowan; Mahmoud A Pouladi; Martina Metzler; Nagat Bissada; Lili Wang; Richard L M Faull; Michelle Gray; X William Yang; Lynn A Raymond; Michael R Hayden |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 30 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-11 Completed Date: 2010-12-13 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 15019-29 Citation Subset: IM |
Affiliation:
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Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics , Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Analysis of Variance Animals Apoptosis / drug effects, genetics* Blotting, Western Caspase 6 / genetics, metabolism* Corpus Striatum / drug effects, metabolism, pathology Disease Progression Humans Huntington Disease / genetics, metabolism*, pathology Immunohistochemistry Mice Mice, Transgenic N-Methylaspartate / pharmacology Nerve Tissue Proteins / genetics, metabolism* Neurons / drug effects, metabolism, pathology Nuclear Proteins / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01 NS049501/NS/NINDS NIH HHS; R01 NS049501-05S1/NS/NINDS NIH HHS; R01 NS049501-06A1/NS/NINDS NIH HHS; R01 NS049501-06A1S1/NS/NINDS NIH HHS; R01 NS049501-07/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Huntington protein, mouse; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 6384-92-5/N-Methylaspartate; EC 3.4.22.-/Caspase 6 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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