TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model.
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.
Khurana
Vikram
V
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.
Lu
Yiran
Y
Steinhilb
Michelle L
ML
Oldham
Sean
S
Shulman
Joshua M
JM
Feany
Mel B
MB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D024801:Tauopathies / Q000378:metabolism* / Q000503:physiopathology
D029721:Drosophila Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; C416303:target of rapamycin protein, Drosophila