Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila
Open accessAbstract
Pathologic alterations in the microtubule-associated protein tau have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). Here, we show that tau overexpression, in combination with phosphorylation by the Drosophila glycogen synthase kinase-3 (GSK-3) homolog and wingless pathway component (Shaggy), exacerbated neurodegeneration induced by tau overexpression alone, leading to neurofibrillary pathology in the fly. Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3beta differs from canonical Wnt effects on beta-catenin stability and TCF activity. The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets.
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In fly neurons, many SP/TP sites are phosphorylated by Sgg.
“In fly neurons, many of these SP/TP sites are phosphorylated by a fly homolog of GSK3 called Sgg [26, 53, 61].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [61]
The Figure 2 legend reports phosphorylated tau in fly retinal neurons when tau and shaggy (Sgg) are coexpressed, and Figure 3 reports increased phosphotau signal in those flies. The paper does not establish that Sgg phosphorylates many SP/TP sites in fly neurons; its fly experiments assess phosphotau with an antibody recognizing a particular epitope, not phosphorylation across many sites. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe gl-tau fly model expresses human wild-type full-length (2N/4R) tau in the eye and causes a rough eye phenotype associated with abnormalities of photoreceptor neurons and other cell types in the underlying retina.
“Our laboratory generated a model of tauopathy in Drosophila melanogaster by expressing human wild-type full-length (2N/4R) tau in the eye using a direct fusion construct of the human tau cDNA to the eye-specific glass (gl) promoter (gl-tau fly). This misexpression causes a rough eye phenotype associated with abnormalities of photoreceptor neurons and other cell types in the underlying retina (47).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [47]
The degree of roughness in the gl-tau fly is intermediate and more pronounced in the anterior eye, making it useful for enhancer-suppressor modifier screens.
“The degree of roughness is intermediate and more pronounced in the anterior eye, making it useful for enhancer–suppressor modifier screens.”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [47]
The data presented here agree with these previous reports and replicate a previous report from our laboratory that LOF of one copy of shaggy suppresses tau toxicity.
“The data presented here agree with these previous reports and replicate a previous report from our laboratory that LOF of one copy of shaggy suppresses tau toxicity (47).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [47]
A direct fusion construct of the human full-length (2N/4R) tau cDNA to the eye-specific glass promoter induces a rough eye phenotype (gl-tau line).
“A direct fusion construct of the human full-length (2N/4R) tau cDNA to the eye-specific glass promoter induces a rough eye phenotype (gl-tau line), as previously described in Jackson et al. (47).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as Jackson et al. [47]
Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases.
“Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases [41, 44, 53, 59–63].”
Canonical Wnt activation leads to the accumulation of β-catenin and inhibition of GSK3β, a critical modulator of tau phosphorylation.
“Canonical Wnt activation leads to the accumulation of β-catenin and inhibition of GSK3β, a critical modulator of tau phosphorylation (Jackson et al., 2002; De Ferrari et al., 2014).”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Jackson et al., 2002
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Br�ckner, G., Grosche, J., Schmidt, S., H�rtig, W., Margolis, R. U., Delpech, B., Seidenbecher, C. I., Czaniera, R., & Schachner, M. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20001225)428:4
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Liu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04391.x · Cited by 759 · see citing works
Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689 · see citing works
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Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
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Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
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Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms
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“NFT-like formation and cell death from tau with no mutations has been shown in a Drosophila model combining overexpression of wild-type human tau with manipulation of GSK3 (glycogen synthase kinase-3 ) activation (Jackson et al., 2002).”
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Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo
DuBoff, B., Götz, J., & Feany, M. B. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.026 · Cited by 377 · see citing works
Oxidative stress mediates tau-induced neurodegeneration in Drosophila
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TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model
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GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila
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Genetic modifiers of tauopathy in Drosophila
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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
Tau protein and neurodegeneration
Goedert, M. (2004) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2003.12.015 · Cited by 177 · see citing works
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Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans
Kraemer, B. C., Burgess, J. K., Chen, J. H., Thomas, J. H., & Schellenberg, G. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl067 · Cited by 150 · see citing works
Karsten, S. L., Sang, T.-K., Gehman, L. T., Chatterjee, S., Liu, J., Lawless, G. M., Sengupta, S., Berry, R. W., Pomakian, J., Oh, H. S., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.019 · Cited by 147 · see citing works
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“Flies were dehydrated in hexamethyldisilazane prior to mounting for SEM as described previously (47).”
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Association of GSK3B with Alzheimer disease and frontotemporal dementia
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Self-citationWnt/&#946;-Catenin Signaling in Alzheimer’s Disease
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“Overexpression of wild-type h-tau or FTDP-17-associated h-tau(R406W) in the fly eye is toxic (Wittmann et al., 2001; Jackson et al., 2002; Nishimura et al., 2004), as indicated by a mild photoreceptor loss (Fig.”
BackgroundDysregulation of tau phosphorylation in mouse brain during excitotoxic damage.
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Modeling the complex pathology of Alzheimer's disease in Drosophila
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- Authors
- Jackson, G. R., Wiedau-Pazos, M., Sang, T.-K., Wagle, N., Brown, C. A., Massachi, S., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Jackson, George R
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 34
- Issue
- 4
- Pages
- 509-519
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2012666269
- Cited by
- 488
- References
- 91
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 18 · 2023: 19 · 2022: 5 · 2021: 13 · 2020: 17 · 2019: 15 · 2018: 10 · 2017: 15 · 2016: 17 · 2015: 12 · 2014: 20 · 2013: 22 · 2012: 16
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 4095 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (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, Shaggy, glycogen synthase kinase-3, Wnt signaling, neurofibrillary pathology, neurodegeneration, Drosophila model, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, β-catenin, disease modifiers
- MeSH terms
- Animals, Cytoskeletal Proteins, Disease Models, Animal, Drosophila melanogaster, Eye Abnormalities, High Mobility Group Proteins, Humans, Mutation, Nervous System Malformations, Phenotype, Repressor Proteins, Transcription Factors, Trans-Activators, Neurofibrillary Tangles, tau Proteins, Apoptosis, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Photoreceptor Cells, Invertebrate, Transgenes, Insect Proteins, Drosophila Proteins, Animals, Genetically Modified, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Inhibitor of Apoptosis Proteins, beta Catenin, Armadillo Domain Proteins
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.
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