Autophagy regulates the processing of amino terminal huntingtin fragments
| Autor: | Leslie M. Thompson, Yumei Wang, Neil Aronin, Marian DiFiglia, Jennifer Yoder, Zheng-Hong Qin, Kimberly B. Kegel, Aleksey G. Kazantsev, Barbara L. Apostol |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Huntingtin animal diseases Cathepsin D Nerve Tissue Proteins Mice mental disorders Autophagy Genetics Huntingtin Protein Animals Humans Molecular Biology Cells Cultured Genetics (clinical) Caspase Cathepsin biology Nuclear Proteins General Medicine Transfection Molecular biology Culture Media nervous system diseases Huntington Disease nervous system Cell culture biology.protein |
| Zdroj: | Human Molecular Genetics. 12:3231-3244 |
| ISSN: | 1460-2083 |
| DOI: | 10.1093/hmg/ddg346 |
| Popis: | The N-terminus of mutant huntingtin (htt) has a polyglutamine expansion and forms neuronal aggregates in the brain of Huntington's disease (HD) patients. Htt expression in vitro activates autophagy, but it is unclear whether autophagic/lysosomal pathways process htt, especially N-terminal htt fragments. We explored the role of autophagy in htt processing in three cell lines, clonal striatal cells, PC12 cells and rodent embryonic cells lacking cathepsin D. Blocking autophagy raised levels of exogenously expressed htt1-287 or 1-969, reduced cell viability and increased the number of cells bearing mutant htt aggregates. Stimulating autophagy promoted htt degradation, including breakdown of caspase cleaved N-terminal htt fragments. Htt expression increased levels of the lysosomal enzyme cathepsin D by an autophagy-dependent pathway. Cells without cathepsin D accumulated more N-terminal htt fragments and cells with cathepsin D were more efficient in degrading wt htt than mutant htt in vitro. These results suggest that autophagy plays a critical role in the degradation of N-terminal htt. Altered processing of mutant htt by autophagy and cathepsin D may contribute to HD pathogenesis. |
| Databáze: | OpenAIRE |
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