Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease
| Autor: | 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, Jeremy M. Van Raamsdonk |
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| Rok vydání: | 2002 |
| Předmět: |
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 |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 22(18) |
| ISSN: | 1529-2401 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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