Notch-1 activation and dendritic atrophy in prion disease
| Autor: | Stanley B. Prusiner, Essia Bouzamondo-Bernstein, Jared L. Clever, Erik Samayoa, Eric J. Huang, Nako Ishikura, Stephen J. DeArmond |
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| Rok vydání: | 2005 |
| Předmět: |
Small interfering RNA
Neurofilament PrPSc Proteins Active Transport Cell Nucleus Mice Inbred Strains Neocortex Receptors Cell Surface Biology Prion Diseases Mice Cell Line Tumor medicine Animals RNA Messenger RNA Small Interfering Receptor Notch1 Neurons Multidisciplinary Neurodegeneration Dendrites Transfection Biological Sciences medicine.disease Virology Cell biology Disease Models Animal Cell nucleus medicine.anatomical_structure Cell culture Female Atrophy Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 102:886-891 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0408612101 |
| Popis: | In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic atrophy is a prominent feature of prion disease. Because increased Notch-1 expression and cleavage releasing its intracellular domain (NICD) inhibit both dendrite growth and maturation, we measured their levels in brains from mice inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was elevated in the neocortex, whereas the level of β-catenin, which stimulates dendritic growth, was unchanged. During the incubation period, levels of the disease-causing prion protein isoform, PrP Sc , and NICD increased concomitantly in the neocortex. Additionally, increased levels of Notch-1 mRNA and translocation of NICD to the nucleus correlated well with regressive dendritic changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was elevated compared with uninfected control (N2a) cells. Long neurofilament protein-containing processes extended from the surface of N2a cells, whereas ScN2a cells had substantially shorter processes. Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype. These results suggest that PrP Sc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells. Whether diminishing Notch-1 activation in vivo can prevent or even reverse neurodegeneration in prion disease remains to be established. |
| Databáze: | OpenAIRE |
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