TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model
| Autor: | Michelle L. Steinhilb, Sean Oldham, Vikram Khurana, Joshua M. Shulman, Mel B. Feany, Yiran Lu |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Blotting
Western Cell Mutant Apoptosis CELLCYCLE Biology MOLNEURO General Biochemistry Genetics and Molecular Biology Phosphatidylinositol 3-Kinases In Situ Nick-End Labeling medicine Animals Drosophila Proteins Neurons Genetics Agricultural and Biological Sciences(all) Biochemistry Genetics and Molecular Biology(all) Kinase TOR Serine-Threonine Kinases Cell Cycle Neurodegeneration Cell cycle medicine.disease Immunohistochemistry Cell biology Enzyme Activation medicine.anatomical_structure Tauopathies Drosophila Tauopathy Signal transduction General Agricultural and Biological Sciences Protein Kinases Signal Transduction |
| Zdroj: | Current Biology. 16:230-241 |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/j.cub.2005.12.042 |
| Popis: | Summary Background Previous studies have demonstrated reexpression of cell-cycle markers within postmitotic neurons in neurodegenerative tauopathies, including Alzheimer's disease (AD). However, the critical questions of whether cell-cycle activation is causal or epiphenomenal to tau-induced neurodegeneration and which signaling pathways mediate cell-cycle activation in tauopathy remain unresolved. Results Cell-cycle activation accompanies wild-type and mutant tau-induced neurodegeneration in Drosophila , and genetically interfering with cell-cycle progression substantially reduces neurodegeneration. Our data support a role for cell-cycle activation downstream of tau phosphorylation, directly preceding apoptosis. We accordingly show that ectopic cell-cycle activation leads to apoptosis of postmitotic neurons in vivo. As in AD, TOR (target of rapamycin kinase) activity is increased in our model and is required for neurodegeneration. TOR activation enhances tau-induced neurodegeneration in a cell cycle-dependent manner and, when ectopically activated, drives cell-cycle activation and apoptosis in postmitotic neurons. Conclusions TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model, identifying TOR and the cell cycle as potential therapeutic targets in tauopathies and AD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|