TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model
Open accessAbstract
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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Pan-neuronal transgenic expression of an FTDP-17 mutant form of human tau, tauR406W, in Drosophila causes progressive neurodegeneration and provides a well-characterized in vivo genetic model of tau neurotoxicity.
“Pan-neuronal transgenic expression of an FTDP-17 mutant form of human tau, tauR406W, in Drosophila causes progressive neurodegeneration and provides a well-characterized in vivo genetic model of tau neurotoxicity7,15,16.”
From Tau promotes neurodegeneration through global chromatin relaxation (2014) · cites this paper as [7]
The Introduction describes transgenic human or mutant tau expression in Drosophila as recapitulating progressive neurodegeneration, and the Results document age-dependent degeneration in tau-expressing flies. The methods identify a panneural expression driver. Our copy does not identify the flies showing these findings as expressing tauR406W, however; the Results explicitly name tauV337M for one genetic experiment. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNo statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported in previous publications.
“No statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported in previous publications 7,16,44.”
From Tau promotes neurodegeneration through global chromatin relaxation (2014) · cites this paper as [7]
Cell cycle activation is causal for neuronal death in tauopathy in Drosophila.
“Studies in Drosophila indicate that cell cycle activation is causal for neuronal death in tauopathy, and that activation of the cell cycle in neurons is sufficient to induce neuronal death18.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [18]
Activation of the cell cycle in neurons is sufficient to induce neuronal death.
“Studies in Drosophila indicate that cell cycle activation is causal for neuronal death in tauopathy, and that activation of the cell cycle in neurons is sufficient to induce neuronal death18.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [18]
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- Authors
- Khurana, V., Lu, Y., Steinhilb, M. L., Oldham, S., Shulman, J. M., & Feany, M. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 16
- Issue
- 3
- Pages
- 230-241
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2064587868
- Cited by
- 266
- References
- 52
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 14 · 2019: 12 · 2018: 14 · 2017: 9 · 2016: 10 · 2015: 18 · 2014: 17 · 2013: 16 · 2012: 18
- FWCI
- 11.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-19790, AG88001, R01AG019790)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- tauopathy, neurodegeneration, TOR signaling, cell cycle re-entry, postmitotic neurons, tau phosphorylation, apoptosis, Alzheimer's disease, Drosophila model, therapeutic target
- MeSH terms
- Animals, Cell Cycle, Drosophila, Enzyme Activation, Immunohistochemistry, Neurons, Protein Kinases, Blotting, Western, Signal Transduction, Apoptosis, Phosphatidylinositol 3-Kinases, In Situ Nick-End Labeling, Tauopathies, Drosophila Proteins, TOR Serine-Threonine Kinases
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