Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin.
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.
MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry (P037), De Crespigny Park, SE5 8AF London, UK. spneici@iop.kcl.ac.uk
Inmaculada
I
Cuchillo-Ibanez
Anjan
A
Seereeram
Helen L
HL
Byers
Kit-Yi
KY
Leung
Malcolm A
MA
Ward
Brian H
BH
Anderton
Diane P
DP
Hanger
D000595:Amino Acid Sequence; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D032701:Biomimetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D013058:Mass Spectrometry; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C489131:Mapt protein, rat; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins; D018021:Lithium Chloride