Human Molecular Genetics Advance Access originally published online on April 29, 2008
Human Molecular Genetics 2008 17(15):2390-2404; doi:10.1093/hmg/ddn139
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Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus
1 Centre for Molecular Medicine and Therapeutics (CMMT), University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4 2 Department of Oral, Biological and Medical Sciences and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Canada V6T 1Z3
* To whom correspondence should be addressed at: Centre For Molecular Medicine and Therapeutics, Children and Family Research Institute, 980 West 28th Avenue, Vancouver, British Columbia V5Z 4H4. Tel: +1 6048753535; Fax: +1 6048753819; Email: mrh{at}cmmt.ubc.ca
Received January 15, 2008; Revised April 21, 2008; Accepted April 28, 2008
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.
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