Tau protein phosphorylation

Itoh N, Arai H, Urakami K, et al. Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer s disease. Ann Neurol 2001 50(2) 150—156. 

Buerger K, Teipel SJ, Zinkowski R, et al. CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002 59(4) 627-629. 

Moller, H. j., Hampel, H. (2003). Differentiation of geriatric major depression from Alzheimer s disease with CSF tau protein phosphorylated at threonine 231. Am.J. Psychiatry 160, 376-379. 

Davies, P. (2001). Tracking of Alzheimer s disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231. Ann. Neurol. 49, 545-546. 

Tau protein phosphorylated at threonine 181 in csf as a neurochemical taomarker in Alzheimer s disease original data and review of the literamre. J. Mol. Neurosci. 

Lovestone S, McLoughUn DM (2002) Protein aggregates and dementia is there a common toxicity J Neurol Neurosurg Psychiatry 72 152-161 Mandelkow EM, Schweers O, Drewes G, Biemat J, Gustke N, Trinczek B et al (1996) Structure, microtubule interactions, and phosphorylation of tau protein. Ann N Y Acad Sci 777 96-106 Mandell JW, Banker GA (1996) A spatial gradient of tau protein phosphorylation in nascent axons. J Neurosci 16 5727-5740... 

Wischik CM, Edwards PC, Lai RY, Gertz HN, Xuereb JH, Paykel ES et al (1995) Quantitative analysis of tau protein in paired helical filament preparations implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer s disease. Neurobiol Aging 16 409-417 discussion 418-31... 

Papasozomenos, S.C. Su, Y. (1991). Altered phosphorylation of tau protein in heat shocked rats and patients with Alzheimer s disease. Proc. Natl. Acad. Sci. USA 88,4543-4547. 

Neurofibrillary tangles are intracellular and consist of abnormally phosphorylated tau protein which is involved in microtubule assembly. Tangles interfere with neuronal function... 

Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pinl restores the functions of Alzheimer-associated phosphorylated tau protein [see comments]. Nature 1999 399 784-788. 

Filamentous tau is hyperphosphorylated. This is an early event that appears to precede filament assembly. It also renders tau unable to interact with microtubules. Much effort has gone into the mapping of phosphorylation sites and the identification of candidate protein kinases and phosphatases. For sites that are also phos-phorylated in normal brain tau, a higher proportion of tau molecules is phosphorylated in filamentous tau. In addition, filamentous tau is phosphorylated at more serine and threonine residues than tau from normal adult brain. Phosphorylation-dependent anti-tau antibodies were instrumental for the study of many phosphorylation sites. In particular, phosphorylation of S214 and S422 was found to be specific for assembled tau. 

Flies and worms. Expression of wild-type and mutant human tau proteins in nerve cells of D. melanogaster and C. elegans led to a reduced lifespan and the loss of nerve cells, in the apparent absence of tau filaments [40, 41]. Phosphorylation of tau was more extensive in the fly than in the worm. In Drosophila, phosphorylation of S262 and S356 in tau by PAR-1 kinase, the fly homologue of MARK, appeared to be necessary for the subsequent phosphorylation at other sites, indicating the existence of a hierarchical and temporally ordered phosphorylation process. 

Lindwall, G. and Cole, R.D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. /. Biol. Chem. 259 5301-5305,1984. 

Isolated microtubules always contain small amounts of larger 300-kDa microtubule-associated proteins (MAPS).330 These elongated molecules may in part lie in the grooves between the tubulin subunits and in part be extended outward to form a low-density layer around the tubule.283 309 Nerve cells that contain stable microtubules have associated stabilizing proteins.331 A family of proteins formed by differential splicing of mRNA are known as tau. The tau proteins are prominent components of the cytoskeleton of neurons. They not only interact with microtubules but also undergo reversible phosphorylation. Hyperphosphorylated tau is the primary component of the paired helical filaments found in the brains of persons with Alzheimer disease.330... 

FIGURE 12-15. Another key finding in Alzheimer s disease is the pathological finding of another degenerative structure called neurofibrillary tangles made up of abnormally phosphorylated tau proteins. 

Baudier J, Mochly-Rosen D, Newton A, Lee SH, Koshland DE, Jr., Cole RD. 1987. Comparison of SlOOb protein with calmodulin interactions with melittin and microtubule-associated tau proteins and inhibition of phosphorylation of tau proteins by protein kinase C. Biochemistry 26(10) 2886-2893. 

Lefebvre, T., Ferreira, S., Dupont-Wallois, L., Bussiere, T., Dupire, M. J., Delacourte, A., et al. (2003) Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins—a role in nuclear localization. Biochim. Biophys. Acta 1619, 167-176. 

As previously described, one of the major neuropathological hallmarks of AD are NFTs. NFTs are composed of paired helical filaments, with the principal protein subunit of paired helical filaments being abnormally hyper-phosphorylated tau (p-tau). Physiologically, tau protein is located in the neuronal axons and in the cytoskeleton. There are six different tau isoforms. Total tau (t-tau) and truncated forms of monomeric and phosphorylated tau are released and can be found in the CSF [71, 80]. 

Maddalena A, Papassotiropoulos A, Muller-Tillmanns B, Jung HH, Hegi T, Nitsch RM, Hock C. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol 2003 60(9) 1202-1206. 

The main characteristic of tauopathies is an age-progressing hyper-phosphorylation of the tau protein which accumulates in tangles with paired helical filaments, twisted ribbons, and/or... 

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