| TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. | |
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MedLine Citation:
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PMID: 16461276 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Vikram Khurana; Yiran Lu; Michelle L Steinhilb; Sean Oldham; Joshua M Shulman; Mel B Feany |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Current biology : CB Volume: 16 ISSN: 0960-9822 ISO Abbreviation: Curr. Biol. Publication Date: 2006 Feb |
Date Detail:
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Created Date: 2006-02-07 Completed Date: 2006-12-04 Revised Date: 2010-02-01 |
Medline Journal Info:
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Nlm Unique ID: 9107782 Medline TA: Curr Biol Country: England |
Other Details:
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Languages: eng Pagination: 230-41 Citation Subset: IM |
Affiliation:
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Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Harvard New Research Building Room 652, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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metabolism* Animals Apoptosis / physiology* Blotting, Western Cell Cycle / physiology* Drosophila Drosophila Proteins / metabolism* Enzyme Activation / physiology Immunohistochemistry In Situ Nick-End Labeling Neurons / cytology, metabolism* Signal Transduction / physiology* Tauopathies / metabolism*, physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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AG19790/AG/NIA NIH HHS; AG88001/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Drosophila Proteins; EC 2.7.1.-/target of rapamycin protein, Drosophila; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase |
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