Document Detail


Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus.
MedLine Citation:
PMID:  18445618     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Proteolysis of mutant huntingtin is crucial to the development of Huntington disease (HD). Specifically preventing proteolysis at the capase-6 (C6) consensus sequence at amino acid 586 of mutant huntingtin prevents the development of behavioural, motor and neuropathological features in a mouse model of HD. However, the mechanism underlying the selective toxicity of the 586 amino acid cleavage event is currently unknown. We have examined the subcellular localization of different caspase proteolytic fragments of huntingtin using neo-epitope antibodies. Our data suggest that the nucleus is the primary site of htt cleavage at amino acid 586. Endogenously cleaved 586 amino acid fragments are enriched in the nucleus of immortalized striatal cells and primary striatal neurons where they co-localize with active C6. Cell stress induced by staurosporine results in the nuclear translocation and activation of C6 and an increase in 586 amino acid fragments of huntingtin in the nucleus. In comparison, endogenous caspase-2/3-generated huntingtin 552 amino acid fragments localize to the perinuclear region. The different cellular itineraries of endogenously generated caspase products of huntingtin may provide an explanation for the selective toxicity of huntingtin fragments cleaved at amino acid 586.
Authors:
Simon C Warby; Crystal N Doty; Rona K Graham; Jeffrey B Carroll; Yu-Zhou Yang; Roshni R Singaraja; Christopher M Overall; Michael R Hayden
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-04-29
Journal Detail:
Title:  Human molecular genetics     Volume:  17     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-07-16     Completed Date:  2008-08-04     Revised Date:  2012-07-11    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  2390-404     Citation Subset:  IM    
Affiliation:
Centre for Molecular Medicine and Therapeutics, University of British Columbia, 980 West 28th Avenue,Vancouver, British Columbia, Canada.
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MeSH Terms
Descriptor/Qualifier:
Active Transport, Cell Nucleus
Amino Acid Sequence
Animals
COS Cells
Caspase 6 / metabolism*
Cell Line
Cell Nucleus / enzymology,  metabolism*
Cercopithecus aethiops
Cytoplasm / enzymology
Enzyme Activation
Humans
Mice
Mice, Transgenic
Molecular Sequence Data
Mutation
Nerve Tissue Proteins / genetics,  metabolism*
Nuclear Proteins / genetics,  metabolism*
Protein Structure, Tertiary
Chemical
Reg. No./Substance:
0/HTT protein, human; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; EC 3.4.22.-/Caspase 6

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