Temporally distinct phosphorylations differentiate Tau-dependent learning deficits and premature mortality in Drosophila
Abstract
Abnormally phosphorylated Tau protein, the major component of neurofibrillary tangles, is critical in the pathogenesis of Alzheimer's disease and related Tauopathies. We used Drosophila to examine the role of key disease-associated phosphorylation sites on Tau-mediated neurotoxicity. We present evidence that the late-appearing phosphorylation on Ser(238) rather than hyperphosphorylation per se is essential for Tau toxicity underlying premature mortality in adult flies. This site is also occupied at the time of neurodegeneration onset in a mouse Tauopathy model and in damaged brain areas of confirmed Tauopathy patients, suggesting a similar critical role on Tau toxicity in humans. In contrast, occupation of Ser(262) is necessary for Tau-dependent learning deficits in adult Drosophila. Significantly, occupation of Ser(262) precedes and is required for Ser(238) phosphorylation, and these temporally distinct phosphorylations likely reflect conformational changes. Because sequential occupation of Ser(262) and Ser(238) is required for the progression from Tau-mediated learning deficits to premature mortality in Drosophila, they may also play similar roles in the escalating symptom severity in Tauopathy patients, congruent with their presence in damaged regions of their brains.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity.
“Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity [26, 53–56].”
Tau phosphorylation at Ser262/356 promotes tau phosphorylation at other SP/TP sites.
“tau phosphorylation at Ser262/356 is reported to promote tau phosphorylation at other SP/TP sites [53, 55]”
Cites
Goedert, M., & Jakes, R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07870.x · Cited by 929 · cited 1× · see citing works
“forms is about one in normal brains, with 4R exhibiting higher affinity for microtubules than 3R in vitro (4).”
BackgroundMonoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205
Goedert, M., Jakes, R., & Vanmechelen, E. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11484-e · Cited by 608 · see citing works
Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms
Andorfer, C., Acker, C. M., Kress, Y., Hof, P. R., Duff, K., & Davies, P. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4637-04.2005 · Cited by 511 · cited 2× · see citing works
“Extensive Ser(238) occupation is observed in older Htau mice, which present strong cognitive deficits and quantitative neuronal loss in their brains (39).”
BackgroundArendt, T., Stieler, J., Strijkstra, A. M., Hut, R. A., Rüdiger, J., Van der Zee, E. A., Harkany, T., Holzer, M., & Härtig, W. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-18-06972.2003 · Cited by 357 · see citing works
Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology
Polydoro, M., Acker, C. M., Duff, K., Castillo, P. E., & Davies, P. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1065-09.2009 · Cited by 329 · see citing works
TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model
Khurana, V., Lu, Y., Steinhilb, M. L., Oldham, S., Shulman, J. M., & Feany, M. B. (2006) · Current Biology · doi:10.1016/j.cub.2005.12.042 · Cited by 266 · see citing works
Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo
Steinhilb, M. L., Dias-Santagata, D., Fulga, T. A., Felch, D. L., & Feany, M. B. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-04-0327 · Cited by 187 · see citing works
Cowan, C. M., Bossing, T., Page, A., Shepherd, D., & Mudher, A. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0716-8 · Cited by 156 · see citing works
Li, T., & Paudel, H. K. (2006) · Biochemistry · doi:10.1021/bi051634r · Cited by 140 · see citing works
Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau
Van der Jeugd, A., Hochgräfe, K., Ahmed, T., Decker, J. M., Sydow, A., Hofmann, A., Wu, D., Messing, L., Balschun, D., D’Hooge, R., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-0987-3 · Cited by 135 · see citing works
Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases
Sergeant, N., David, J.-P., Lefranc, D., Vermersch, P., Wattez, A., & Delacourte, A. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00859-4 · Cited by 117 · see citing works
Iijima-Ando, K., Zhao, L., Gatt, A., Shenton, C., & Iijima, K. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq068 · Cited by 72 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005917 · Cited by 105 · see citing works
- Authors
- Papanikolopoulou, K., & Skoulakis, E. M. C.
- Affiliations
- Alexander Fleming Biomedical Sciences Research Center (GR)
- Corresponding author
- Papanikolopoulou, Katerina
- Skoulakis, Efthimios M.C.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-12-18
- Volume
- 24
- Issue
- 7
- Pages
- 2065-2077
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2147811302
- Cited by
- 33
- References
- 12
- Citations by year
- 2025: 3 · 2023: 3 · 2022: 5 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 1
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, tau phosphorylation, tauopathy, Alzheimer's disease, neurofibrillary tangles, Drosophila, learning deficits, premature mortality, neurotoxicity, conformational change
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Learning, Male, Middle Aged, Phosphorylation, Neurofibrillary Tangles, tau Proteins, Amino Acid Motifs, Mice, Mortality, Premature
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
