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Dissociation of tau toxicity and phosphorylation: role of GSK-3β, MARK and Cdk5 in a Drosophila model

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Chatterjee, Shreyasi, Sang, Tzu-Kang, Lawless, George M., Jackson, George R.·2009·Human Molecular Genetics
DOI 10.1093/hmg/ddn326PMC PMC2644648
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Abstract

Hyperphosphorylation of tau at multiple sites has been implicated in the formation of neurofibrillary tangles in Alzheimer's disease; however, the relationship between toxicity and phosphorylation of tau has not been clearly elucidated. Putative tau kinases that play a role in such phosphorylation events include the proline-directed kinases glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent kinase 5 (Cdk5), as well as nonproline-directed kinases such as microtubule affinity-regulating kinase (MARK)/PAR-1; however, whether the cascade of events linking tau phosphorylation and neurodegeneration involves sequential action of kinases as opposed to parallel pathways is still a matter of controversy. Here, we employed a well-characterized Drosophila model of tauopathy to investigate the interdependence of tau kinases in regulating the phosphorylation and toxicity of tau in vivo. We found that tau mutants resistant to phosphorylation by MARK/PAR-1 were indeed less toxic than wild-type tau; however, this was not due to their resistance to phosphorylation by GSK-3beta/Shaggy. On the contrary, a tau mutant resistant to phosphorylation by GSK-3beta/Shaggy retained substantial toxicity and was found to have increased affinity for microtubules compared with wild-type tau. The fly homologs of Cdk5/p35 did not have major effects on tau toxicity or phosphorylation in this model. These data suggest that, in addition to tau phosphorylation, microtubule binding plays a crucial role in the regulation of tau toxicity when misexpressed. These data have important implications for the understanding and interpretation of animal models of tauopathy.

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  • S11A demonstrates severe toxicity when expressed in the eye, producing an even smaller and rougher eye than wild-type tau.

    “Instead of alleviating toxicity, S11A demonstrates severe toxicity when expressed in the eye, producing an even smaller and rougher eye than wild-type tau (42).”

    From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [42]

    The Results section describes S11A-expressing flies as having reduced, rough eyes with fused ommatidia and missing bristles. The Discussion says the S11A eye phenotype was, in several instances, as severe as that of wild-type tau; it does not support the claim that S11A produced an even smaller and rougher eye than wild-type tau. Page numbers were not available in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • 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].”

    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 [26]

    The Results sections on S2A tau identify Ser262/356 as PAR-1 phosphorylation sites and report that the phosphorylation-resistant mutant was less toxic than wild-type tau in the fly eye. The claim overstates the GSK3-target-site part: the Discussion reports substantial toxicity in tau resistant to GSK-3β/Shaggy phosphorylation, while the Results report relatively normal eyes despite elevated phosphorylation at GSK-3β-relevant epitopes. No page numbers are available in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Phosphorylation at Ser262 and Ser356 decreases tau binding to microtubules.

    “Ser262 and Ser356 are located in the microtubule-binding domain, and phosphorylation at these sites decreases tau binding to microtubules [18, 19, 25, 26, 50, 51].”

    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 [26]

    The Results section ('Misexpression of PAR-1 but not Shaggy produces neurodegeneration'; page unavailable) places Ser262 and Ser356 in tau’s microtubule-binding region. But the microtubule-binding Results do not show that phosphorylation at those sites decreases binding: the S2A mutant, which resists phosphorylation at those sites, bound somewhat less avidly than wild-type tau. The paper describes detachment after hyperphosphorylation as a theory not yet proven in intact animal or human studies. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In vivo fly models of tau toxicity using phosphorylation-resistant tau constructs show equivalent or even increased toxicity when compared with wild-type tau.

    “in vivo fly models of tau toxicity using phosphorylation-resistant tau constructs show equivalent or even increased toxicity when compared with wild-type tau (41,42).”

    From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [42]

  • GSK-3β phosphorylation of tau was independent of phosphorylation by PAR-1.

    “However, our laboratory observed that GSK-3β phosphorylation of tau was independent of phosphorylation by PAR-1 (42).”

    From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [42]

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Authors
Chatterjee, S., Sang, T.-K., Lawless, G. M., & Jackson, G. R.
Affiliations
  • University of California, Los Angeles (US)
  • National Tsing Hua University (TW)
Corresponding author
Jackson, George R.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2008-10-17
Volume
18
Issue
1
Pages
164-177
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddn326
PMC
PMC2644648
OpenAlex
W2157578198
Cited by
178
References
9
Citations by year
2026: 10 · 2025: 15 · 2024: 9 · 2023: 11 · 2022: 3 · 2021: 9 · 2020: 6 · 2019: 11 · 2018: 5 · 2017: 8 · 2016: 15 · 2015: 5 · 2014: 13 · 2013: 14 · 2012: 10
FWCI
7.70
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institute on Aging (AG-016570, P50AG016570)
  • National Institute of Neurological Disorders and Stroke (R01NS046489, NS 046489)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
tau phosphorylation, tau toxicity, tauopathy, Alzheimer's disease, neurofibrillary tangles, GSK3β, cyclin-dependent kinase 5, Shaggy, microtubule binding, Drosophila model, kinase cascade
MeSH terms
Alzheimer Disease, Animals, Drosophila melanogaster, Eye, Humans, Microtubules, Phosphorylation, Protein Binding, tau Proteins, Protein Serine-Threonine Kinases, Mutation, Missense, Drosophila Proteins, Animals, Genetically Modified, Glycogen Synthase Kinase 3, Cyclin-Dependent Kinase 5

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