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J. Biol. Chem., Vol. 282, Issue 32, 23645-23654, August 10, 2007

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Novel Phosphorylation Sites in Tau from Alzheimer Brain Support a Role for Casein Kinase 1 in Disease Pathogenesis^*

Diane P. Hanger¹², Helen L. Byers¹, Selina Wray, Kit-Yi Leung³, Malcolm J. Saxton, Anjan Seereeram, C. Hugh Reynolds, Malcolm A. Ward, and Brian H. Anderton

From the MRC Centre for Neurodegeneration Research, Department of Neuroscience and Proteome Sciences plc, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, United Kingdom

Tau in Alzheimer disease brain is highly phosphorylated and aggregated into paired helical filaments comprising characteristic neurofibrillary tangles. Here we have analyzed insoluble Tau (PHF-tau) extracted from Alzheimer brain by mass spectrometry and identified 11 novel phosphorylation sites, 10 of which were assigned unambiguously to specific amino acid residues. This brings the number of directly identified sites in PHF-tau to 39, with an additional six sites indicated by reactivity with phosphospecific antibodies to Tau. We also identified five new phosphorylation sites in soluble Tau from control adult human brain, bringing the total number of reported sites to nine. To assess which kinases might be responsible for Tau phosphorylation, we used mass spectrometry to determine which sites were phosphorylated in vitro by several kinases. Casein kinase 1 and glycogen synthase kinase-3 were each found to phosphorylate numerous sites, and each kinase phosphorylated at least 15 sites that are also phosphorylated in PHF-tau from Alzheimer brain. A combination of casein kinase 1 and glycogen synthase kinase-3 activities could account for over three-quarters of the serine/threonine phosphorylation sites identified in PHF-tau, indicating that casein kinase 1 may have a role, together with glycogen synthase kinase-3, in the pathogenesis of Alzheimer disease.

Received for publication, April 18, 2007 , and in revised form, June 7, 2007.

^* This work was supported by grants from the MRC, the Alzheimer's Society, and the Progressive Supranuclear Palsy Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S10.

¹ Both authors contributed equally to this work.

³ Present address: William Harvey Research Institute, Barts and the London, Charterhouse Square, EC1M 6BQ London, UK.

² To whom correspondence should be addressed. Tel.: 44-20-7848-0041; Fax: 44-20-7708-0017; E-mail: d.hanger{at}iop.kcl.ac.uk.

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