Hyper-phosphorylation

The large subimit of RNA polymerase II plays an important role at the beginning of the transcription process. The large subimit of the mammalian enzyme contains 52 copies of the heptamer sequence YSPTSPS in the C-terminal domain (CTD) at which phosphorylation occurs. Phosphorylation occurs extensively on the Ser-residues of the CTD, to a lesser degree at the Thr-residues, and, very rarely, at the Tyr-residues. Two forms of RNA polymerase II can be isolated from cellular extracts a underphosphory-lated form and a hyper-phosphorylated form. The isoforms fulfill different functions RNA polymerase found in the initiation complex tends to display little or no phosphorylation at the C-terminus of the large subunit, while RNA polymerase II active in elongation is hyperphosphorylated in this region of the protein. 

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]. 

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... 

AD Af and hyper-phosphorylated tau Cortex, hippocampus, basal forebrain Neuritic plaques and neurofibrillary tangles... 

According to the amyloid hypothesis, abnormalities involving AP peptides also lead to changes in the organization of tau to produce neun>fibriilary tangles, the lesion in brain tissue that is more closely associated with the presence of clinical AD, Deposition of tau in tangles i.s enhanced by tau hyper-phosphorylation, which can be accomplished by a variety... 

TTP is an extraordinarily low-abundance, inducible, stable cytosolic, and hyper-phosphorylated mRNA binding protein [24,25, 31-33]. TTP mRNA and protein... 

The inability to induce Akt hyperphosphorjdation through inhibition of downstream components of the Akt pathway led us to investigate a non-pathway-based mechanism of dmg-induced Akt hyperphosphorjd-ation. Indeed, we observed indistinguishable dmg-induced Akt hyper-phosphorylation whether the kinase was active and able to transduce signals downstream in the pathway or whether it was inactive. 

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