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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.08-109181v1 fj.08-109181v2 22/9/3186    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cuchillo-Ibanez, I. Articles by Hanger, D. P. Search for Related Content PubMed PubMed Citation Articles by Cuchillo-Ibanez, I. Articles by Hanger, D. P.

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

¹Correspondence: MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry (P037), De Crespigny Park, SE5 8AF London, UK. E-mail: spneici{at}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