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Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo |
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| Authors: | Amandine Jullienne Axel Montagne Cyrille Orset Flavie Lesept David E Jane Daniel T Monaghan Eric Maubert Denis Vivien Carine Ali |
| Institution: | 1. MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, King’s College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK 6. Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL, UK 3. Department of Neurology, King’s College London, CHU de Nantes, F-44000, France 2. Proteome Sciences plc, Institute of Psychiatry, King’s College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK 7. Institute of Child Health, University College London, Guilford Street, London, WC1N 1EH, UK 8. Division of Basic Medical Sciences, St. George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK 4. Yamanouchi Research Institute, Armstrong Road, Littlemore Park, Oxford, OX4 4SX, UK 9. Current Medicine Group, 11-21 Paul Street, London, EC2A 4JU, UK 10. Johnson and Johnson Pharmaceutical Research and Development, Turnhoutsweg 30, Beerse, B-2340, Belgium 5. School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, QLD4072, Australia 11. Biomedical Research Institute, Ninewells Medical School, University of Dundee, Dundee, DD1 9SY, UK |
| Abstract: | BackgroundTau protein is the principal component of the neurofibrillary tangles found in Alzheimer's disease, where it is hyperphosphorylated on serine and threonine residues, and recently phosphotyrosine has been demonstrated. The Src-family kinase Fyn has been linked circumstantially to the pathology of Alzheimer's disease, and shown to phosphorylate Tyr18. Recently another Src-family kinase, Lck, has been identified as a genetic risk factor for this disease.ResultsIn this study we show that Lck is a tau kinase. In vitro, comparison of Lck and Fyn showed that while both kinases phosphorylated Tyr18 preferentially, Lck phosphorylated other tyrosines somewhat better than Fyn. In co-transfected COS-7 cells, mutating any one of the five tyrosines in tau to phenylalanine reduced the apparent level of tau tyrosine phosphorylation to 25-40% of that given by wild-type tau. Consistent with this, tau mutants with only one remaining tyrosine gave poor phosphorylation; however, Tyr18 was phosphorylated better than the others.ConclusionsFyn and Lck have subtle differences in their properties as tau kinases, and the phosphorylation of tau is one mechanism by which the genetic risk associated with Lck might be expressed pathogenically. |
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