101. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease
- Author
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Juliette Gafni, Simon C. Warby, Claire-Anne Gutekunst, Lisa M. Ellerby, Yu-Zhou Yang, Donald W. Nicholson, Steven M. Hersch, Roshni R. Singaraja, Odell Loubser, Blair R. Leavitt, Cheryl L. Wellington, Dale E. Bredesen, Michael R. Hayden, Rona K. Graham, Sophie Roy, Daniel A. Rogers, and Jeremy M. Van Raamsdonk
- Subjects
Genetically modified mouse ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,animal diseases ,Mice, Transgenic ,Nerve Tissue Proteins ,Cysteine Proteinase Inhibitors ,Cleavage (embryo) ,Kidney ,Transfection ,Antibodies ,Cell Line ,Mice ,Mice, Neurologic Mutants ,Huntington's disease ,Antibody Specificity ,mental disorders ,medicine ,Animals ,Humans ,ARTICLE ,Chromosomes, Artificial, Yeast ,Caspase ,Brain Chemistry ,Neurons ,Huntingtin Protein ,biology ,General Neuroscience ,Neurodegeneration ,Brain ,Nuclear Proteins ,Human brain ,Polyglutamine tract ,medicine.disease ,Molecular biology ,Caspase Inhibitors ,Peptide Fragments ,nervous system diseases ,Disease Models, Animal ,Kinetics ,medicine.anatomical_structure ,Huntington Disease ,nervous system ,Caspases ,Mutation ,biology.protein ,Disease Progression ,Trinucleotide Repeat Expansion - Abstract
Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552. We detect caspase-cleaved htt in control human brain as well as in HD brains with early grade neuropathology, including one homozygote. Cleaved htt is also seen in wild-type and HD transgenic mouse brains before the onset of neurodegeneration. These results suggest that caspase cleavage of htt may be a normal physiological event. However, in HD, cleavage of mutant htt would release N-terminal fragments with the potential for increased toxicity and accumulation caused by the presence of the expanded polyglutamine tract. Furthermore, htt fragments were detected most abundantly in cortical projection neurons, suggesting that accumulation of expanded htt fragments in these neurons may lead to corticostriatal dysfunction as an early event in the pathogenesis of HD.
- Published
- 2002