Low Levels of Mutant Ubiquitin Are Degraded by the Proteasome In Vivo
| Autor: | Paula van Tijn, Marian C. Verhage, Fred W. van Leeuwen, Barbara Hobo, David F. Fischer |
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| Přispěvatelé: | Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Netherlands Institute for Neuroscience (NIN) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Genetically modified mouse
Aging Proteasome Endopeptidase Complex Serine Proteinase Inhibitors Transgene Lactacystin Mutant Population Radioimmunoassay Mice Transgenic Biology Cell Line Cellular and Molecular Neuroscience chemistry.chemical_compound Mice neurodegenerative disease Ubiquitin mutant ubiquitin medicine Animals RNA Messenger education education.field_of_study Reverse Transcriptase Polymerase Chain Reaction proteasome inhibitor Molecular biology Immunohistochemistry Cell biology Acetylcysteine transgenic mouse model chemistry Proteasome Calcium-Calmodulin-Dependent Protein Kinases Proteasome inhibitor biology.protein ubiquitin-proteasome system medicine.drug |
| Zdroj: | Journal of Neuroscience Research, 88(11), 2325-2337. Wiley-Liss Inc. Journal of Neuroscience Research, 88, 2325-2337. Wiley-Liss Inc. |
| ISSN: | 0360-4012 |
| Popis: | The ubiquitin-proteasome system fulfills a pivotal role in regulating intracellular protein turnover. Impairment of this system is implicated in the pathogenesis of neurodegenerative diseases characterized by ubiquitin- containing proteinaceous deposits. UBB(+1), a mutant ubiquitin, is one of the proteins accumulating in the neuropathological hallmarks of tauopathies, including Alzheimer's disease, and polyglutamine diseases. In vitro, UBB(+1) properties shift from a proteasomal ubiquitin-fusion degradation substrate at low expression levels to a proteasome inhibitor at high expression levels. Here we report on a novel transgenic mouse line (line 6663) expressing low levels of neuronal UBB(+1). In these mice, UBB(+1) protein is scarcely detectable in the neuronal cell population. Accumulation of UBB(+1) commences only after intracranial infusion of the proteasome inhibitors lactacystin or MG262, showing that, at these low expression levels, the UBB(+1) protein is a substrate for proteasomal degradation in vivo. In addition, accumulation of the protein serves as a reporter for proteasome inhibition. These findings strengthen our proposition that, in healthy brain, UBB(+1) is continuously degraded and disease-related UBB(+1) accumulation serves as an endogenous marker for proteasomal dysfunction. This novel transgenic line can give more insight into the intrinsic properties of UBB(+1) and its role in neurodegenerative disease. |
| Databáze: | OpenAIRE |
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