Reference Work Entry

Encyclopedia of Genetics, Genomics, Proteomics and Informatics

pp 1935-1936

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TAU (MAPT, 17q21.1)

The size of the tau gene can vary from ∼352 to 441 amino acids in the isoforms of the microtubule-associated proteins by alternative splicing of the mRNA (Margittai M, Langen R 2004 Proc Natl Acad Sci USA 101:10278).

By reducing motor reattachment rates, tau affects cargo travel distance, motive force, and cargo dispersal. Different isoforms of tau, at concentrations similar to those in cells, have dramatically different potency.

These defined mechanism show how altered tau isoform levels could impair transport and thereby lead to neurodegeneration without the need of any other pathway (Vershinin M et al 2007 Proc Natl Acad Sci USA 104:87). It seems to form tangles by virtue of the 306Val-Gln-Ile-Val-Tyr-Lys311 motif in the 6 tau monomers in several types of nerve degenerative diseases (e.g., Pick disease, Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration).

A pseudogene exists at 6q21. Base substitution and splice site mutations may lead to Pick disease, parkinsonism and Alzheimer’s disease. In the tangle of the paired helical filaments, tau is hyperphosphorylated causing defects in microtubule assembly and mitotic arrest. The use of a kinase inhibitor (at lysine 252) can prevent hyperphosphorylation of tau and the aggregation of tau without reducing the tangles; such a treatment reduces severe motor function impairment in transgenic mice indicating that aggregation rather than tangling is the cause of the development of tau pathology (Le Corre S et al 2006 Proc Natl Acad Sci USA 103:9673).

The adverse effect of hyperphosphorylation may be prevented by trimethylamine N-oxide (TMAO) because this natural compound lowers the concentration of tubulin needed for assembly. The hyperphosphorylated tau may self-assemble and the causes the fibrillary tangle observed in the degenerated brain of Alzheimer’s patients. Cyclic-AMP-dependent protein kinase (PKA), glycogen synthase kinase 3β (GSK-3β), or Cdk5 may carry out the phosphorylation.

Phosphorylation of a Ser or a Thr amino acid preceding a Pro creates a binding site for the prolyl-isomerase Pin1. When Pin1 binds to this site in tau, it may deplete it in the brain leading to some of the problems related with Alzheimer’s disease. Amyloid-β immunotherapy can clear the fibrillar tangle with the aid of proteasomes, if applied before the hyperphosphorylation of tau (Oddo S et al 2004 Neuron 43:321). In human Parkinsonism, mutation can affect aberrant splicing of exon 10. Using a spliceosome-mediated trans-splicing, the mRNA can be reprogrammed. Thus, creating a new exon 9–exon 10 junction indicates the feasibility of therapeutic trans-splicing (Rogriguez-Martin T et al 2005 Proc Natl Acad Sci USA 102:15659). Neurofibrillary degeneration is increased when both Aβ and tau are expressed the same time. In a mouse model of Alzheimer’s disease, the chronic supply of nicotine exacerbates tau tangles (Oddo S et al 2005 Proc Natl Acad Sci USA 102:3046). In mouse transgenic for a suppressible tau, memory was recovered and neuron numbers were stabilized after suppression of tau, yet neurofibrillary tangles continued to grow, indicating that the tangles are not sufficient to account for the degenerative phenomena (see Fig. T19) (SantaCruz K et al 2005 Science 309:476). Fragments of the repeat domain of tau, containing mutations of FTDP17 (frontotemporal dementia with Parkinsonism linked to chromosome 17 also called Pick disease), produced by endogenous proteases, can induce the aggregation of full-length tau. Fragments are generated by successive cleavages, first N-terminally between lysine257 and serine258, then C-terminally around residues 353–364; conversely, when the N-terminal cleavage is inhibited, no fragmentation and aggregation takes place. The C-terminal truncation and the coaggregation of fragments with full-length tau depend on the propensity for β-structure. The aggregation is modulated by phosphorylation but does not depend on it. Aggregation but not fragmentation is toxic to cells; conversely, inhibiting either aggregation or proteolysis can prevent toxicity (Wang YP et al 2007 Proc Natl Acad Sci USA 104:10252). In a Drosophila model of tauopathy, neurodegenerative symptoms appeared without the fibrillary tangle. FTDP-17, prion, amyloids, secretase, sirtuin, Pick disease, Alzheimer disease, p35, parkinsonism, microtubule, CDK, palsy, corticobasal degeneration, synuclein, RNAi, trans-splicing; von Bergen M et al 2000 Proc Natl Acad Sci USA 97:5129; Wittmann CW et al 2001 Science 293:711; Lewis J et al 2001 Science 293:1487; Liou Y-C et al 2003 Nature [Lond] 424:556.
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Figure T19.

Transgenic mouse brain expressing neurofibrillary tangle (enlarged in insert) and Aβ plaques similar that occurs in humans afflicted by Alzheimer disease. (Courtesy of Drs. Dennis W. Dickson and Wen-lang Lin, Mayo Clinic, Jacksonville, Florida; I am indebted also to Mike Hampton, Maryland)

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