Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau

Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau are classified as tauopathies. hyperphosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites which are targeted by protein kinases such as GSK3β and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced by Pin1 a peptidyl-prolyl isomerase that stimulates dephosphorylation at proline-directed sites by protein phosphatase 2A. Pin1 deficiency is suggested to cause Tau hyperphosphorylation in Alzheimer disease. Up to the present Pin1 binding was only shown for two Tau phosphorylation sites (Thr-212 and Thr-231) Rabbit monoclonal to IgG (H+L)(HRPO). despite the presence of many more hyperphosphorylated sites. Here we analyzed the conversation of Pin1 with Tau phosphorylated by Cdk5-p25 using a GST pulldown assay and Biacore approach. We found that Pin1 binds and stimulates dephosphorylation of Tau at all Cdk5-mediated sites (Ser-202 Thr-205 Ser-235 and Ser-404). Furthermore FTDP-17 mutant Tau (P301L or R406W) showed slightly weaker Pin1 binding than non-mutated Tau suggesting that FTDP-17 mutations induce hyperphosphorylation by reducing the conversation between Pin1 and Tau. Together these results indicate that Pin1 is generally involved in the regulation of Tau hyperphosphorylation and hence the etiology of tauopathies. gene and is characterized by lesions made up of hyperphosphorylated Tau (3-5). Genetically modified mice featuring the mutations of FTDP-17 developed comparable aggregates of hyperphosphorylated Tau and showed dementia-like memory impairments indicating a causative role of the mutations (2 6 7 However it is not yet known why these Tau mutations induce Tau aggregation and neurodegeneration. Understanding the molecular mechanisms that induce Tau hyperphosphorylation and aggregation in AD and FTDP-17 may be critical to unravel the processes underlying the etiology of tauopathies. Tau in neurofibrillary tangles is usually phosphorylated at more than 30 sites with most of them being located 24, 25-Dihydroxy VD3 in the flanking regions of the microtubule-binding repeats (8-10). Many protein kinases have been implicated in Tau phosphorylation. Proline-directed protein kinases (PDPKs) such as glycogen synthase 24, 25-Dihydroxy VD3 kinase 3β (GSK3β) and cyclin-dependent kinase 5 (Cdk5) have been thought to be critically involved in abnormal Tau phosphorylation because many proline-directed sites are hyperphosphorylated in Tau (2 8 10 Cdk5 originally purified as Tau kinase II (13) is usually a serine/threonine kinase with pleiotropic functions in postmitotic neurons (14 15 Cdk5 needs binding from the activation subunit p35 for activation. The energetic holoenzyme Cdk5-p35 can be localized towards the cell membrane via the myristoylation of p35 (16-18). Membrane-associated Cdk5-p35 displays moderate kinase activity because of a brief half-life of p35 which can be degraded from the proteasome (19). On the other hand p35 could be cleaved to p25 by calpain as well as the Cdk5-p25 holoenzyme can consequently relocalize towards the cytoplasm and/or nucleus (16 20 21 The Cdk5 activator p25 includes a lengthy half-life (16 21 and induces aberrant Cdk5 activity toward Tau (22 23 Regularly silencing of Cdk5 decreased the phosphorylation of Tau in major neuronal ethnicities and in mind and decreased the amount of neurofibrillary tangles in the hippocampi of transgenic 24, 25-Dihydroxy VD3 Alzheimer disease mice (24). Nonetheless it isn’t very clear how Cdk5-p25 causes Tau aggregation and hyperphosphorylation. In FTDP-17 24, 25-Dihydroxy VD3 individuals and transgenic mouse versions Tau can be hyperphosphorylated (2 8 10 11 25 On the other hand FTDP-17 mutant Tau can be much less phosphorylated than wild-type (WT) Tau or in cell ethnicities (26-29). These research claim that disruption of dephosphorylation than improved phosphorylation plays a part in the hyperphosphorylated state of Tau rather. Accordingly proteins phosphatase 2A (PP2A) activity can be decreased in Advertisement brains (30-32) and extremely phosphorylated Tau in combined helical filament can be fairly resistant to dephosphorylation 24, 25-Dihydroxy VD3 by PP2A (33). Furthermore PP2A preferentially dephosphorylated phospho-(Ser/Thr)-Pro motifs in conformation when artificial phospho-Thr-231 Tau peptide was utilized like a substrate (34 35 Peptidyl-prolyl isomerase NIMA-interacting 1 (Pin1) can be a peptidylprolyl isomerase.