a(HBP:"paired helical filaments")

Entity

Name

paired helical filaments

Namespace

HBP

Namespace Version

20190126

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/77c0796c3ca82a80cb0eaf1c8380d6ccd7f323af/export/hbp-names.belns

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics. PubMed:7667312

Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics. PubMed:7667312

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process PubMed:8391280

Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process PubMed:8391280

Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process PubMed:8391280

Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics. PubMed:7667312

Studies in transgenic mice and in cell cultures have shown a connection between PP2A loss of function and tau hyper-phosphorylation and aggregation into PHF. PubMed:22299660

Polyclonal antibodies to the classical paired helical filaments (PHFs) found in the neurofibrillary tangles and dystrophic neurites of AD were first raised in about 1982, allowing exploration of the component(s) of PHFs using immunochemical approaches (Ihara et al. 1983) PubMed:22908190

Polyclonal antibodies to the classical paired helical filaments (PHFs) found in the neurofibrillary tangles and dystrophic neurites of AD were first raised in about 1982, allowing exploration of the component(s) of PHFs using immunochemical approaches (Ihara et al. 1983) PubMed:22908190

Besides the characteristic “PHF smear,” they also labeled a very small protein of ~8 kDa. Hiroshi Mori named these monoclonal antibodies DF (Dementia Filament) 1 and 2, of which the latter (DF2) was used for subsequent characterization (Mori et al. 1987). PubMed:22908190

PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000). PubMed:22908190

This protein reactive with the initial anti-PHF sera was soon identified as tau, a microtubule-associated protein (MAP), based on its molecular weight, isoform change during development, microtubule- binding activity, and heat stability (Kosik et al. 1986; Nukina and Ihara 1986; see also Brion et al. 1985; Grundke-Iqbal et al. 1986; Wood et al. 1986; discovery of tau in PHF is reviewed in Mandelkow and Mandelkow 2011). PubMed:22908190

Using well-characterized antibodies to various MAPs as well as PHF polyclonal antibodies, tau had recently been established as a major component of PHFs (see above and Mandelkow and Mandelkow 2011). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed. PubMed:22908190

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed. PubMed:22908190

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed. PubMed:22908190

In human AD brains, but not in normal brains, tau is modified by N‑glycosylation, which is proposed to help to maintain and stabilize PHF structure PubMed:26631930

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

They present evidence that paired helical filaments obtained from AD brain or generated in vitro can inhibit proteasome function and that in AD brain tissue these filaments coimmunoprecipitate with the proteasome (Keck et al., 2003). PubMed:14556719

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics. PubMed:7667312

Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process PubMed:8391280

Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process PubMed:8391280

Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process PubMed:8391280

Studies in transgenic mice and in cell cultures have shown a connection between PP2A loss of function and tau hyper-phosphorylation and aggregation into PHF. PubMed:22299660

Polyclonal antibodies to the classical paired helical filaments (PHFs) found in the neurofibrillary tangles and dystrophic neurites of AD were first raised in about 1982, allowing exploration of the component(s) of PHFs using immunochemical approaches (Ihara et al. 1983) PubMed:22908190

Polyclonal antibodies to the classical paired helical filaments (PHFs) found in the neurofibrillary tangles and dystrophic neurites of AD were first raised in about 1982, allowing exploration of the component(s) of PHFs using immunochemical approaches (Ihara et al. 1983) PubMed:22908190

This protein reactive with the initial anti-PHF sera was soon identified as tau, a microtubule-associated protein (MAP), based on its molecular weight, isoform change during development, microtubule- binding activity, and heat stability (Kosik et al. 1986; Nukina and Ihara 1986; see also Brion et al. 1985; Grundke-Iqbal et al. 1986; Wood et al. 1986; discovery of tau in PHF is reviewed in Mandelkow and Mandelkow 2011). PubMed:22908190

Using well-characterized antibodies to various MAPs as well as PHF polyclonal antibodies, tau had recently been established as a major component of PHFs (see above and Mandelkow and Mandelkow 2011). PubMed:22908190

Besides the characteristic “PHF smear,” they also labeled a very small protein of ~8 kDa. Hiroshi Mori named these monoclonal antibodies DF (Dementia Filament) 1 and 2, of which the latter (DF2) was used for subsequent characterization (Mori et al. 1987). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993). PubMed:22908190

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed. PubMed:22908190

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed. PubMed:22908190

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed. PubMed:22908190

PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000). PubMed:22908190

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930