Premium
Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin
Author(s) -
CuchilloIbanez Inmaculada,
Seereeram Anjan,
Byers Helen L.,
Leung KitYi,
Ward Malcolm A.,
Anderton Brian H.,
Hanger Diane P.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-109181
Subject(s) - phosphorylation , axoplasmic transport , gsk 3 , dephosphorylation , neurodegeneration , kinesin , tau protein , serine , chemistry , threonine , microbiology and biotechnology , microtubule , hyperphosphorylation , kinase , biochemistry , biology , phosphatase , alzheimer's disease , medicine , disease
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 hyperphos‐phorylated 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 de‐phosphorylated 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. FASEB J. 22, 3186–3195 (2008)