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Annalisa Cavallini Suzanne Brewerton Amanda Bell Samantha Sargent Sarah Glover Clare Hardy Roger Moore John Calley Devaki Ramachandran Michael Poidinger Eric Karran Peter Davies Michael Hutton Philip Szekeres Suchira Bose 《The Journal of biological chemistry》2013,288(32):23331-23347
Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3β, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3β using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies. 相似文献
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Phosphorylation of proteasomes in mammalian cells 总被引:2,自引:0,他引:2
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Benjamin Falcon Annalisa Cavallini Rachel Angers Sarah Glover Tracey K. Murray Luanda Barnham Samuel Jackson Michael J. O'Neill Adrian M. Isaacs Michael L. Hutton Philip G. Szekeres Michel Goedert Suchira Bose 《The Journal of biological chemistry》2015,290(2):1049-1065
Intracellular Tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer disease, tangle-only dementia, Pick disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled “prion-like” species. Several cell and animal models have been described that recapitulate aspects of this phenomenon. However, the molecular characteristics of seed-competent Tau remain unclear. Here, we have used a cell model to understand the relationships between Tau structure/phosphorylation and seeding by aggregated Tau species from the brains of mice transgenic for human mutant P301S Tau and full-length aggregated recombinant P301S Tau. Deletion of motifs 275VQIINK280 and 306VQIVYK311 abolished the seeding activity of recombinant full-length Tau, suggesting that its aggregation was necessary for seeding. We describe conformational differences between native and synthetic Tau aggregates that may account for the higher seeding activity of native assembled Tau. When added to aggregated Tau seeds from the brains of mice transgenic for P301S Tau, soluble recombinant Tau aggregated and acquired the molecular properties of aggregated Tau from transgenic mouse brain. We show that seeding is conferred by aggregated Tau that enters cells through macropinocytosis and seeds the assembly of endogenous Tau into filaments. 相似文献
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Hong Wang Yupeng Li John W. Ryder Justin T. Hole Philip J. Ebert David C. Airey Hui-Rong Qian Benjamin Logsdon Alice Fisher Zeshan Ahmed Tracey K. Murray Annalisa Cavallini Suchira Bose Brian J. Eastwood David A. Collier Jeffrey L. Dage Bradley B. Miller Kalpana M. Merchant Michael J. O’Neill Ronald B. Demattos 《Molecular neurodegeneration》2018,13(1):65
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