Lysosomal proteases are involved in generation of N-terminal huntingtin fragments
| Autor: | Ellen Sapp, Kimberly B. Kegel, Neil Aronin, Yun Joong Kim, Marian DiFiglia, Benjamin G. Cuiffo, Peter J. Detloff, Jennifer Yoder, Lindsay Sobin, Zheng-Hong Qin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Huntingtin
medicine.medical_treatment Cathepsin D Mice Transgenic Nerve Tissue Proteins Biology Cathepsin B Cathepsin C lcsh:RC321-571 Mice Mice Neurologic Mutants Cathepsin O medicine Animals Aspartic Acid Endopeptidases Enzyme Inhibitors Cleavage products A and B lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cathepsin S Cell Line Transformed Cathepsin Neurons Huntingtin Protein Protease Binding Sites Cysteine proteases Cathepsins B and L Nuclear Proteins Molecular biology Cathepsins Corpus Striatum Peptide Fragments Protein Structure Tertiary Mice Inbred C57BL Huntingtin proteolysis Huntington Disease Neurology Mutation Aspartyl proteases Lysosomes Peptide Hydrolases |
| Zdroj: | Neurobiology of Disease, Vol 22, Iss 2, Pp 346-356 (2006) |
| Popis: | N-terminal mutant huntingtin (N-mhtt) fragments form inclusions and cause cell death in vitro. Mutant htt expression stimulates autophagy and increases levels of lysosomal proteases. Here, we show that lysosomal proteases, cathepsins D, B and L, affected mhtt processing and levels of cleavage products (cp) known as A and B, which form inclusions. Adding inhibitors of cathepsin D, B and L to clonal striatal cells reduced mhtt, especially mhtt fragment cp A. Mutant htt fully degraded in cathepsin-L-treated lysates but formed stable N-mhtt fragments upon exposure to cathepsin D. Mutagenesis analysis of htt cDNA suggested that cathepsin D and the protease for cp A may cleave htt in the same region. Brain lysates from HD knock-in mice expressed N-mhtt fragments that accumulated with cathepsin D treatment and declined with aspartyl protease inhibition. Findings implicate lysosomal proteases in formation of N-mhtt fragments and clearance of mhtt. |
| Databáze: | OpenAIRE |
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