Phosphorylation of Tau Protein with a Novel Tau Protein Kinase Forming Paired Helical Filament Epitopes on Tau
In aged human brain and particularly in Alzheimer’s disease brain, paired helical filaments (PHF’s) accumulate in the neuronal cells. Recently, it was discovered that tau protein is a component of PHF. Tau protein is one of the brain-specific, microtubule-associated proteins (MAP’s) and promotes the formation of microtubules in vitro and in vivo. Several groups found using antibodies that the tau in PHF is highly phosphorylated. Y. Ihara et al.1 showed that anti PHF polyclonal antibodies contain an antibody reacting with phosphorylated tau (p-tau) but not with dephosphorylated tau (dp-tau). Grundke-Iqbal et al.2 reported that monoclonal antibody to tau, tau-1, reacted with PHF, and reacted even more strongly with dephosphorylated PHF. Normally, tau is associated with microtubules and easily solubilized. However, tau in PHF is unusually insoluble, thus giving rise to the following question: how is tau incorporated into PHF to become an insoluble form? We assume that the phosphorylation of tau is the cause of PHF formation. To study the mechanism underlying accumulation of PHF’s, we purified and characterized a novel protein kinase that phosphorylates tau protein to form PHF epitopes, and studied properties of tau phosphorylated by the kinase.
KeywordsPhosphorylation Site Brain Extract Paired Helical Filament Microtubule Formation Aged Human Brain
Unable to display preview. Download preview PDF.
- 1.Y. Ihara, N. Nukina, R. Miura, and M. Ogawara. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J. Biochem. (Tokyo) 99: 1807–1810 (1986).Google Scholar
- 2.I. Grundke-Iqbal, K. Igbal, Y. -C. Tung, M. Quinlan, H. M. Winsniewski, and L.I. Binder. Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 83:4913–4917 (1986).Google Scholar
- 3.K. Ishiguro, Y. Ihara, T. Uchida, and K. Imahori. A novel tubulin- dependent protein kinase forming a paired helical filament epitopes on tau. J. Biochem. (Tokyo) 104: 319–321 (1988).Google Scholar
- 4.K. S. Kosik, L. D. Orecchio, L. Binder, J. Q. Trojanowski, V. M. -Y. Lee, and G. Lee. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1: 817–825 (1988).Google Scholar
- 5.V. M. -Y. Lee, L. Otvos, Jr., M. J. Carden, M. Hollosi, B. Dietzschold, and R.A. Lazzarini. Identification of the major multiphosphorylation site in mammalian neurofilaments. Proc. Natl. Acad. Sci. USA 85: 1998–2002 (1988).Google Scholar
- 6.K. Iqbal, I. Grundke-Iqbal, A. J. Smith, L. George, Y. -C. Tung, and T. Zaidi. Identification and localization of a T peptide to paired helical filaments of Alzheimer disease. Proc. Natl. Acad. Sci. USA 86:5646–5650 (1989).Google Scholar
- 8.S. A. Lewis, D. Wang, and N. J. Cowan. Microtubule-associated protein MAP2 shares a microtubule binding motif with tau protein. Science 242: 936–939 (1988).Google Scholar
- 9.C. M. Wischik, M. Novak, H. C. Thagersen, P. C. Edwards, M. J. Runswick, R. Jakes, J. E. Walker, C. Milstein, M. Roth, and A. Klug. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. USA 85: 4506–4510 (1988).CrossRefGoogle Scholar
- 10.Y. Uchida, Y. Ihara, and M. Tomonaga. Alzheimer’s disease brain extract stimulates the survival fo cerebral cortical neurons from neonatal rats. Biochem. Biophys. Res. Commun. 150: 1263–1267 (1988).Google Scholar
- 11.Y. Ihara. Massive somatodendritic sprouting of cortical neurons in Alzheimer’s disease. Brain Res. 459: 138–144 (1988).Google Scholar