Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin Inmaculada Cuchillo-Ibanez * ,1 , Anjan Seereeram * , Helen L. Byers † , Kit-Yi Leung † ,2 , Malcolm A. Ward † , Brian H. Anderton * and Diane P. Hanger * * Medical Research Council Centre for Neurodegeneration Research and † Proteome Sciences, King’s College London, Institute of Psychiatry, London, UK 1 Correspondence: MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry (P037), De Crespigny Park, SE5 8AF London, UK. E-mail: spneici@iop.kcl.ac.uk Defective axonal transport has been proposed as an underlying mechanism that may give rise to neurodegeneration. We investigated the effect of phosphorylation on the axonal transport of tau, a neuronal protein that stabilizes microtubules and is hyperphosphorylated and mislocalized in Alzheimer’s disease. We report here that specific inhibition of glycogen synthase kinase-3 (GSK-3) reduces tau phosphorylation and significantly decreases the overall rate of axonal transport of tau in rat cortical neurons. Tau mutants, with serine/threonine targets of GSK-3 mutated to glutamate to mimic a permanent state of phosphorylation, were transported at a significantly increased rate compared to wild-type tau. Conversely, tau mutants, in which alanine replaced serine/threonine to mimic permanent dephosphorylation, were transported at a decreased rate compared to wild-type tau. We also found that tau interacts with the light chain of kinesin-1 and that this is dependent on the phosphorylation state of tau. Tau phosphorylation by GSK-3 increased binding, and dephosphorylated tau exhibited a reduced association with kinesin-1. We conclude that GSK-3 phosphorylation of tau modulates its axonal transport by regulating binding to kinesin-1. Hyperphosphorylated tau in Alzheimer’s disease appearing first in distal portions of axons may result from aberrant axonal transport of phosphorylated tau reported here.—Cuchillo-Ibanez, I., Seereeram, A., Byers, H. L., Leung, K.-Y., Ward, M. A., Anderton, B. H., Hanger, D. P. Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin. Key Words: GSK-3 • mass spectrometry • lithium
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Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin
Cuchillo-Ibanez, Inmaculada; Seereeram, Anjan; Byers, Helen L.; Leung, Kit-Yi; Ward, Malcolm A.; Anderton, Brian H.; Hanger, Diane P.
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, Volume 22 (9): 3186
Fed of American Socs for Experimental Biology – Sep 1, 2008
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