| Background. Previous studies have demonstrated re-expression 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.; Methods. Genetic analysis in Drosophila is well suited to address the issue of causality and is utilized here to address these questions. Key features of human tauopathies, including tau hyperphosphorylation and progressive neurodegeneration, are recapitulated by transgenic expression of human or mutant wild-type tau. Furthermore, fly and mammalian cell-cycle machineries are substantially conserved, as are mitogenic signaling pathways including the TOR pathway. Thus, the relationship between tau-induced neurodegeneration, cell-cycle activation and mitogenic signaling pathways in vivo can appropriately be investigated in flies.; 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. In addition, inhibition of cell-cycle checkpoints substantially enhances tau-induced neurodegeneration in the fly brain, indicating a potential protective role for checkpoint proteins against aberrant mitogenic stress in adult postmitotic neurons. 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. Other signaling molecules that activate TOR also enhance tau-induced neurodegeneration. Finally, mutation of all five tyrosine residues of tau to phenylalanine does not prevent cell-cycle activation, indicating that direct interactions between tau and SH2 domain-containing proteins are not a requirement for cell-cycle activation.; Conclusions. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model and cell-cycle checkpoints protect against tau-induced neurodegeneration in vivo . Our data identify TOR and the cell cycle as potential therapeutic targets in tauopathies and AD. |
