PAR-1 Kinase Plays an Initiator Role in a Temporally Ordered Phosphorylation Process that Confers Tau Toxicity in Drosophila
Open accessAbstract
Multisite hyperphosphorylation of tau has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). However, the phosphorylation events critical for tau toxicity and mechanisms regulating these events are largely unknown. Here we show that Drosophila PAR-1 kinase initiates tau toxicity by triggering a temporally ordered phosphorylation process. PAR-1 directly phosphorylates tau at S262 and S356. This phosphorylation event is a prerequisite for the action of downstream kinases, including glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase-5 (Cdk5), to phosphorylate several other sites and generate disease-associated phospho-epitopes. The initiator role of PAR-1 is further underscored by the fact that mutating PAR-1 phosphorylation sites causes a much greater reduction of overall tau phosphorylation and toxicity than mutating S202, one of the downstream sites whose phosphorylation depends on prior PAR-1 action. These findings begin to differentiate the effects of various phosphorylation events on tau toxicity and provide potential therapeutic targets.
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par-1 and shaggy are known tau kinases.
“Two modifiers identified in an unbiased manner from these screens, par-1 and shaggy, are known tau kinases (24,25,90–92)”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [92]
Increased par-1 expression increases tau toxicity.
“Both Nishimura et al. (92) and Chatterjee et al. (42) reported that increased par-1 expression increases tau toxicity”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [92]
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].”
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].”
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]”
Drosophila PAR-1 kinase is a functional homolog of MARKs and is the major kinase of human tau at Ser262 and Ser356 expressed in fly eye and brain.
“Drosophila PAR-1 kinase, a functional homolog of MARKs, is the major kinase of human tau at Ser262 and Ser356 expressed in fly eye and brain [53, 63]”
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].”
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- Authors
- Nishimura, I., Yang, Y., & Lu, B.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Lu, Bingwei
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 116
- Issue
- 5
- Pages
- 671-682
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1998276610
- Cited by
- 324
- References
- 7
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 11 · 2022: 7 · 2021: 6 · 2020: 14 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 14 · 2015: 9 · 2014: 14 · 2013: 15 · 2012: 13
- FWCI
- 17.69
- 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, 3916 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
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau phosphorylation, tau toxicity, Alzheimer's disease, glycogen synthase kinase-3, cyclin-dependent kinase 5, Drosophila, therapeutic target
- MeSH terms
- Animals, Drosophila melanogaster, Phenotype, Phosphorylation, Protein Kinases, Signal Transduction, Mutagenesis, Site-Directed, tau Proteins, Protein Serine-Threonine Kinases, Photoreceptor Cells, Invertebrate, Cyclin-Dependent Kinases, Neurodegenerative Diseases, Drosophila Proteins, Animals, Genetically Modified, Glycogen Synthase Kinase 3, Cyclin-Dependent Kinase 5
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