a(HBP:"Tau epitope, 12E8")

Entity

Name

Tau epitope, 12E8

Namespace

HBP

Namespace Version

20181119

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/90e1cb9e5e882703380c9db8d4915ac6f3cba137/export/hbp-names.belns

Activating autophagy with trehalose in rat cortical neurons demonstrated certain phospho-epitopes (AT8, PHF1, and 12E8) were reduced more significantly than total tau – up to 80% compared to the 20% reduction in total tau (96). PubMed:24027553

When corrected for the difference in total Tau, 12E8 phosphorylation does not differ between proaggregant and antiaggregant Tau (Fig. 2C) PubMed:27671637

When corrected for the difference in total Tau, 12E8 phosphorylation does not differ between proaggregant and antiaggregant Tau (Fig. 2C) PubMed:27671637

We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites PubMed:22156579

We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events PubMed:25031639

In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90 PubMed:25031639

Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. PubMed:22156579

In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90 PubMed:25031639

When corrected for the difference in total Tau, 12E8 phosphorylation does not differ between proaggregant and antiaggregant Tau (Fig. 2C) PubMed:27671637

When corrected for the difference in total Tau, 12E8 phosphorylation does not differ between proaggregant and antiaggregant Tau (Fig. 2C) PubMed:27671637

We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites PubMed:22156579

We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events PubMed:25031639

In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90 PubMed:25031639