Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity

In the paper

“GSK3 is a proline-directed kinase that contributes to phosphorylation of tau at serine or threonine followed by proline (i.e., SP/TP sites) [46–49]”

What the sources say

• ?Not checked — no full text of the sourcecites [46] F Hernandez, 2010, GSK3: a possible link between beta amyloid peptide and tau protein, Exp Neurol source
• Partly supported

  The Results identify GSK3β as TPKI and report that TPKI phosphorylates tau at specific serine and threonine residues, supporting its role in tau phosphorylation. The passages do not identify those residues as SP/TP sites or describe GSK3β as proline-directed, so that specificity is not established by our copy. (LLM, conf=0.83)

  cites [47] K Ishiguro, 1993, Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments, FEBS Lett sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report increased tau phosphorylation at several serine and threonine sites in cells expressing GSK3β. The introduction says GSK3α has been suggested to act as a proline-directed threonine kinase, but says GSK3β’s site specificity was not fully elucidated. The paper therefore supports GSK3β’s contribution to tau phosphorylation, but does not establish the claimed SP/TP specificity for GSK3β. (LLM, conf=0.86)

  cites [48] BR Sperber, 1995, Glycogen synthase kinase-3 beta phosphorylates tau protein at multiple sites in intact cells, Neurosci Lett sourceExperimental — accuracy not yet measured
• Supported

  In the discussion (page unavailable), the paper identifies tau Thr111 as adjacent to proline and says GSK-3β was likely responsible for its phosphorylation. The Results also report numerous tau sites phosphorylated by GSK-3β. This supports the claim that GSK3 contributes to phosphorylation at SP/TP sites; the paper does not suggest it acts only at those sites. (LLM, conf=0.84)

  cites [49] DP Hanger, 2007, Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis, J Biol Chem source

In the paper

“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”

What the sources say

• ?Not checked — no full text of the sourcecites [2] M Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
• ?Not checked — no full text of the sourcecites [35] J Busciglio, 1995, beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding, Neuron source
• ?Not checked — no full text of the sourcecites [36] A Ferreira, 1997, Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta, Mol Cell Neurosci source
• ?Not checked — no full text of the sourcecites [37] A Takashima, 1998, Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons, Neurosci Res source
• Partly supported

  Figure 5 reports increased tau Ser422 phosphorylation after Aβ oligomer treatment in cultured neurons, and the Discussion reports increased phosphorylated tau in a 3xTg-AD mouse model under a high-fat diet. The Discussion says GSK3β is known to be activated by Aβ, but predicts rather than demonstrates its activation through the mechanism studied here. The cited passages do not establish that Aβ co-expression increases active GSK3 and PAR-1/MARK; PAR-1/MARK is not reported. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [38] QL Ma, 2009, Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin, J Neurosci sourceExperimental — accuracy not yet measured
• Partly supported

  In “Synapses disappear in regions of Tau missorting” (page unavailable), the paper reports increased Tau phosphorylation and strong local activation of MARK after Aβ-oligomer treatment. It explicitly says GSK3β activity remained unchanged. The experiments described used treated cultured neurons, not co-expression of Aβ in both cellular and animal models. (LLM, conf=0.90)

  cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci sourceExperimental — accuracy not yet measured
• Partly supported

  Results §3.3 reports increased tau phosphorylation at Thr231 and Ser404 after Aβ-oligomer exposure in cultured rat hippocampal neurons. The Introduction also reports prior findings of GSK-3β activation and describes transgenic mice expressing APP and tau. However, this paper does not show that Aβ co-expression increases active GSK3 in its models, and the cited passages do not establish an increase in active PAR-1/MARK. (LLM, conf=0.88)

  cites [40] FG De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [41] J Folwell, 2010, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp Neurol source
• ?Not checked — no full text of the sourcecites [43] QL Ma, 2006, Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro, J Neurosci Res source
• Partly supported

  The Discussion reports that Aβ42 increased tau phosphorylation in earlier cell and mouse studies, and that Arctic Aβ42 increased GSK-3 activity in this paper's flies. But the Results found no increase in phosphorylation at the tested Ser262 and Ser356 tau sites in those flies; the paper identifies these as MARK substrates without reporting increased PAR-1/MARK activity. The citation therefore supports only part of the combined claim. (LLM, conf=0.86)

  cites [44] O Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet sourceExperimental — accuracy not yet measured

In the paper

“Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases [41, 44, 53, 59–63].”

What the sources say

• ?Not checked — no full text of the sourcecites [41] J Folwell, 2010, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp Neurol source
• Partly supported

  The Introduction describes human-tau fly models with neuronal dysfunction and reports that co-expression with Shaggy, a conserved GSK-3 homologue, worsens neurotoxic phenotypes. It does not establish progressive neurodegeneration or show that conserved kinases phosphorylate human tau at AD-related sites in those models. The Results examine phosphorylation sites on endogenous fly tau instead and find no change at the Ser262 or Ser356 homologous epitopes under the conditions tested. No page numbers are available in our copy. (LLM, conf=0.85)

  cites [44] O Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [53] I Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source
• ?Not checked — no full text of the sourcecites [59] CW Wittmann, 2001, Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles, Science source
• ?Not checked — no full text of the sourcecites [60] A Mudher, 2004, GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila, Mol Psychiatry source
• Supported

  The discussion (page unavailable in our copy) describes the tau-expressing fly eye phenotype as involving progressive neurodegeneration. The section on GSK-3β/shaggy identifies shaggy as the fly counterpart of a human tau kinase, and Figure 2 reports tau aggregates recognized by an antibody to a phosphorylated, Alzheimer’s-related epitope when shaggy is coexpressed. (LLM, conf=0.90)

  cites [61] GR Jackson, 2002, Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila, Neuron source
• Supported

  The Introduction (page unavailable) describes age-dependent neurodegeneration in Drosophila tau models. The phosphorylation results and Discussion (page unavailable) report phosphorylation of human Tau at AD-associated sites in fly neurons and identify Tau-targeting kinases, including GSK-3β. The paper cautions that phosphorylation varies by cell type, but that does not undermine the broad claim about these models. (LLM, conf=0.88)

  cites [62] S Grammenoudi, 2006, Cell type-specific processing of human Tau proteins in Drosophila, FEBS Lett source
• Supported

  The Results report age-dependent, progressive neurodegeneration in flies expressing human tau. They also report phosphorylation at the AD-related Ser262 site and show that PAR-1, a homolog of mammalian MARK, mediates its increase after milton knockdown. The phosphorylation finding is specific to that site and condition, rather than every AD-related site. (LLM, conf=0.89)

  cites [63] K Iijima-Ando, 2012, Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1, PLoS Genet source

In the paper

“suggesting that the neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau [11–14].”

What the sources say

• Supported

  In “Soluble tau: Evidence for toxicity” (page unavailable), the paper reports neurodegeneration in Drosophila models without insoluble tau and says this is strong evidence that soluble tau can cause toxicity. The same section describes soluble tau species appearing at very early disease stages, supporting the claim’s hedged suggestion about early tau toxicity. (LLM, conf=0.88)

  cites [11] CM Cowan, 2013, Are tau aggregates toxic or protective in tauopathies?, Frontiers in neurology source
• ?Not checked — no full text of the sourcecites [12] N Sahara, 2008, Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration, Curr Alzheimer Res source
• ?Not checked — no full text of the sourcecites [13] KV Kuchibhotla, 2014, Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo, Proc Natl Acad Sci U S A source
• ?Not checked — no full text of the sourcecites [14] K Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source

In the paper

“Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”

What the sources say

• ?Not checked — no full text of the sourcecites [2] M Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
• ?Not checked — no full text of the sourcecites [35] J Busciglio, 1995, beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding, Neuron source
• ?Not checked — no full text of the sourcecites [36] A Ferreira, 1997, Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta, Mol Cell Neurosci source
• ?Not checked — no full text of the sourcecites [37] A Takashima, 1998, Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons, Neurosci Res source
• Partly supported

  The Results section on cultured hippocampal neurons (page unavailable) reports that Aβ42 oligomers significantly increased tau phosphorylation at Ser422, a site the paper associates with AD neurodegeneration. The paper also reports increased tau Ser422 phosphorylation in 3xTg-AD mice on a high-fat diet, but it does not establish that Aβ itself caused that increase in vivo. (LLM, conf=0.84)

  cites [38] QL Ma, 2009, Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin, J Neurosci sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Figure 5 passage report that Aβ oligomers increased tau phosphorylation at AD-associated epitopes, including 12E8 and AT8, in cultured hippocampal neurons. The paper’s experimental model was in vitro; it does not establish the claimed effect in an in vivo model. (LLM, conf=0.88)

  cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (§3.3; page unavailable) show that Aβ oligomers increased phosphorylation at the AD-associated Thr231 and Ser404 sites in cultured neurons. The Introduction (§1; page unavailable) reports tau hyperphosphorylation after Aβ injection in animals, but does not establish phosphorylation at those specific sites in vivo; this paper's own experiments were in vitro. (LLM, conf=0.82)

  cites [40] FG De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [41] J Folwell, 2010, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp Neurol source

In the paper

“Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”

What the sources say

• ?Not checked — no full text of the sourcecites [2] M Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
• ?Not checked — no full text of the sourcecites [3] J Lewis, 2001, Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP, Science source
• ?Not checked — no full text of the sourcecites [4] J Gotz, 2001, Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils, Science source
• ?Not checked — no full text of the sourcecites [5] S Oddo, 2004, Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome, Neuron source
• ?Not checked — no full text of the sourcecites [6] DJ Selkoe, 2011, Resolving controversies on the path to Alzheimer's therapeutics, Nat Med source
• ?Not checked — no full text of the sourcecites [7] ED Roberson, 2007, Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model, Science source
• Supported

  The Abstract (page not provided) says genetic evidence strongly supports Aβ accumulation as causative in AD. “The intersection of Aβ and tau at the synapse” describes a model in which tau alterations occur downstream of Aβ-induced changes, while noting that further studies are needed; the claim’s “suggests” reflects that uncertainty. (LLM, conf=0.88)

  cites [8] TL Spires-Jones, 2014, The intersection of amyloid beta and tau at synapses in Alzheimer's disease, Neuron source
• ?Not checked — no full text of the sourcecites [9] A Caccamo, 2005, Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders, Neurobiol Aging source
• Supported

  The citation is attached to the claim that Aβ lies upstream of tau-induced neurodegeneration. The Discussion reports that reducing soluble Aβ in ArcTau mice reduced tau pathology and cognitive decline, and concludes that Aβ can drive tau pathogenesis and contribute to tau-mediated neuronal dysfunction in AD. (LLM, conf=0.88)

  cites [10] MA Chabrier, 2012, Soluble abeta promotes wild-type tau pathology in vivo, J Neurosci source

In the paper

“the activities of two major tau kinases, GSK3 and PAR-1/microtubule affinity-regulating kinases (MARKs), are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity [37, 39, 43–45].”

What the sources say

• ?Not checked — no full text of the sourcecites [37] A Takashima, 1998, Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons, Neurosci Res source
• Partly supported

  In the Discussion and Figure 6, the paper links Aβ-induced MARK/Par-1 activity to tau detachment from microtubules and microtubule destabilization. It does not support the same association for GSK3β in this experiment: the Discussion says GSK3β activity did not increase in dendrites with missorted tau. (LLM, conf=0.88)

  cites [39] H Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [43] QL Ma, 2006, Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro, J Neurosci Res source
• Partly supported

  The Introduction links Aβ to increased tau phosphorylation and GSK-3 activation; the Discussion identifies MARK as a kinase that phosphorylates tau. But the paper does not establish that either kinase causes tau to detach from microtubules or that PAR-1/MARK augments Aβ-induced tau toxicity. In its fly model, the Discussion reports no observable change in overall tau phosphorylation with Aβ42 expression. (LLM, conf=0.84)

  cites [44] O Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and the section ‘Expression of non-phosphorylatable form of tau blocks Aβ toxicity’ link PAR-1/MARK-mediated tau phosphorylation to tau toxicity and Aβ-induced synaptic and spine damage (page numbers unavailable). Our copy does not establish the corresponding role for GSK3 or state that either kinase causes tau to detach from microtubules. (LLM, conf=0.87)

  cites [45] W Yu, 2012, A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses and dendritic spines, Hum Mol Genet sourceExperimental — accuracy not yet measured

In the paper

“In Drosophila, tau phosphorylation at proline-directed Ser and Thr (SP/TP) sites decreases tau binding to microtubules, whereas replacing these phosphorylation sites with unphosphorylatable Ala significantly increases binding [25, 26].”

What the sources say

• ?Not checked — no full text of the sourcecites [25] S Feuillette, 2010, Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein, J Neurochem source
• Supported

  The Results section, “Microtubule binding of S2A tau is reduced, whereas that of S11A is increased compared with wild-type tau” (page not provided), reports significantly greater microtubule binding for the alanine-substituted S11A tau. The Discussion, “Perspectives on the relationship between tau phosphorylation and toxicity in the context of animal models” (page not provided), says proline-directed kinases release tau from microtubules and that inability to be phosphorylated by Shaggy may cause S11A tau to remain bound. (LLM, conf=0.91)

  cites [26] S Chatterjee, 2009, Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model, Hum Mol Genet source

In the paper

“The majority of tau species (including tau lacking phosphorylation at Ser262/356) are degraded by the proteasome [20], while aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system [79–84].”

What the sources say

• ?Not checked — no full text of the sourcecites [79] CA Dickey, 2006, HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites, FASEB J source
• Partly supported

  The paper’s discussion of tau degradation (page unavailable) says aggregated tau is removed by macroautophagy and tau phosphorylated at KXGS motifs in the repeat domains can be degraded by the autophagy-lysosomal system. Our copy does not identify Ser262/356 specifically, so it does not establish that site-specific part of the claim. (LLM, conf=0.82)

  cites [80] Y Wang, 2010, Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation, Autophagy sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion states that tau phosphorylated at KXGS motifs is degraded by autophagy rather than the proteasome, and §3.4 reports increased soluble Ser262/356-phosphorylated tau after autophagy inhibition. These passages support the phosphorylated-tau part of the claim, but our copy does not establish that aggregated tau is degraded by the autophagy-lysosome system; the study reports no change in insoluble tau after VCP knockdown. (LLM, conf=0.87)

  cites [81] PJ Dolan, 2011, Decreases in valosin-containing protein result in increased levels of tau phosphorylated at Ser262/356, FEBS Lett sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [82] T Hamano, 2008, Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression, Eur J Neurosci source
• Partly supported

  In “Rapamycin enhances clearance of tau and decreases tau toxicity in vivo” (pp. 4–5), rapamycin reduced aggregate-prone or insoluble tau, and blocking autophagy abolished its effect on insoluble tau. The paper does not identify phosphorylation at Ser262/356, and it says mutant tau can be degraded by autophagy when induced but is not predominantly degraded that way under basal conditions. (LLM, conf=0.88)

  cites [83] Z Berger, 2006, Rapamycin alleviates toxicity of different aggregate-prone proteins, Human Molecular Genetics sourceExperimental — accuracy not yet measured
• Partly supported

  The Results ('Autophagy mediates the degradation of phosphorylated tau'; page unavailable) show that blocking autophagy or lysosomal function attenuated phosphorylated-tau degradation. The Discussion reports reduced Ser262/356-phosphorylated tau after Nrf2 activation or NDP52 overexpression. The Results ('NDP52 decreases sarkosyl-insoluble tau in AD cases'; page unavailable) link NDP52 to less insoluble tau, but suggest prevention of aggregation through phosphorylated-tau clearance rather than demonstrating degradation of already aggregated tau. (LLM, conf=0.85)

  cites [84] C Jo, 2014, Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52, Nature communications sourceExperimental — accuracy not yet measured

In the paper

“Consistent with this, the autophagic system and endosome/lysosome pathways are compromised in AD brains, and chronic disturbance of this system is thought to contribute to protein accumulation and neurodegeneration [85–87].”

What the sources say

• ?Not checked — no full text of the sourcecites [85] RA Nixon, 2007, Autophagy, amyloidogenesis and Alzheimer disease, J Cell Sci source
• Partly supported

  The Background reports macroautophagy defects in brain sections from patients with AD and discusses disruption of the macroautophagy–lysosomal pathway. It also presents defective protein degradation as a possible contributor to pathological inclusions. The cited passages do not establish that the endosomal pathway is compromised in AD brains. (LLM, conf=0.84)

  cites [86] K Inoue, 2012, Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway, Mol Neurodegener sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s introductory discussion (page not available) describes excess autophagosomes in affected AD neurons and suggests defects in their removal. Its Discussion links altered autophagy to tau accumulation and possible neurodegeneration. It does not establish that endosome/lysosome pathways themselves are compromised in AD brains; its evidence about those pathways concerns how CALM regulates autophagy. (LLM, conf=0.83)

  cites [87] K Moreau, 2014, PICALM modulates autophagy activity and tau accumulation, Nature communications sourceExperimental — accuracy not yet measured

In the paper

“Drosophila PAR-1 kinase, a functional homolog of MARKs, is the major kinase of human tau at Ser262 and Ser356 expressed in fly eye and brain [53, 63]”

What the sources say

• ?Not checked — no full text of the sourcecites [53] I Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source
• Partly supported

  The Results section on PAR-1 and Ser262 identifies MARK as the mammalian homolog of Drosophila PAR-1 and says PAR-1 knockdown reduces tau phosphorylation at Ser262, suggesting it is the major Ser262 kinase in the fly eye. The paper does not establish that PAR-1 is the major kinase at Ser356 or that this major-kinase finding applies to the fly brain. (LLM, conf=0.88)

  cites [63] K Iijima-Ando, 2012, Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1, PLoS Genet sourceExperimental — accuracy not yet measured

In the paper

“In contrast to PAR-1/MARK, blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity.”

In the paper

“Tau proteins expressed in the fly retina are detected as two major bands by western blotting with pan-tau antibody (Fig 1B).”

In the paper

“Western blotting with TAU-1 antibody, which specifically recognizes tau protein without phosphorylation at several AD-related sites (Ser194, Ser195, Ser198, and Ser202), detected taulower (Fig 1C, TAU-1)”

In the paper

“We found that the levels of tau in the cytosol fraction were significantly elevated, whereas the levels in the microtubule fraction were reduced, in the fly retina co-expressing Aβ42 and tau (Fig 1B).”

In the paper

“blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231”

In the paper

“co-expression of Aβ42 did not significantly change the levels of tubulin in the form of microtubules (Fig 1B, tubulin) or the levels of acetylated or tyrosinated tubulin (S4 Fig)”

In the paper

“the effects were smaller than those in wild-type tau: Aβ42 caused a 3-fold increase in the level of wild-type tauupper in the cytosol (Fig 1B), but only a 1.6-fold increase in the level of S2A tauupper (Fig 3F, right).”

In the paper

“knockdown of Sgg significantly decreased phosphorylation levels of tau at SP/TP sites and shifted all tau species to lower–molecular weight regions (Fig 2)”

In the paper

“PAR-1 knockdown reduced the levels of tau (Fig 5C, tauC/Tau46), and the reductions in the levels of taulower were more prominent than those of tauupper (Fig 5C, tauC/Tau46,).”

In the paper

“although Aβ42 still increased the level of S2A tauupper in the cytosol and decreased that in the microtubule fraction (Fig 3F)”

In the paper

“In vivo microtubule-binding assays revealed that, in the GSK3/Sgg knockdown background, co-expression of Aβ42 was still capable of increasing the level of tau in the cytosolic fraction and decreasing the level in the microtubule fraction (Fig 2D).”

In the paper

“Under this experimental condition, expression of neither Aβ42 alone nor Aβ42 with GSK3β/Sgg RNAi caused a reduction in eye size (S6 Fig)”

In the paper

“Moreover, the SDS-PAGE migration pattern of S2A tau differed from that of wild-type tau.”

In the paper

“when the phosphorylation levels of S2A tau at Ser202 were normalized against total levels of S2A tau, they were not elevated; instead, they were reduced relative to those of wild-type tau (Fig 3B and 3E).”

In the paper

“whereas PAR-1/MARKs are non-SP/TP kinases that phosphorylate tau at Ser262 and Ser356 in the repeat domains located in the microtubule-binding region [50].”

What the sources say

• ?Not checked — no full text of the sourcecites [50] G Drewes, 1997, MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption, Cell source

In the paper

“These results suggest that, regardless of its phosphorylation status, microtubule-unbound free tau in the cytosol is more abundant in the presence of Aβ42.”

In the paper

“However, the roles of, and interdependency between, tau phosphorylation by GSK3 and MARK/PAR-1 in an early step of tau mismetabolism, such as tau mislocalization and stabilization of mislocalized tau, are not fully understood.”

In the paper

“These results raise the possibility that the difference between the original taulower and tauupper species includes not only phosphorylation status at GSK3-target sites but also additional post-transcriptional modifications and/or differences in cellular localization.”

In the paper

“One of the membranes was probed with anti-tubulin, and used as the loading control for other blots in each experiment.”

In the paper

“All experiments were performed using age-matched male flies, and genotypes are described in S1 Table.”

In the paper

“Taken together, these data demonstrate that S2A mutation preferentially reduces the levels of taulower, and partially suppresses the Aβ42-mediated increase in the levels of tau mislocalized from the microtubule to the cytosol.”

In the paper

“Western blots were repeated a minimum of three times with different animals and representative blots are shown.”

In the paper

“Taken together, these results suggest that blocking tau phosphorylation at GSK3/Sgg sites is not sufficient to suppress either mislocalization of tau to the cytosol or Aβ42-induced augmentation of tau toxicity.”

In the paper

“This study highlights the critical roles of tau phosphorylation at Ser262/356 in stabilization of tau and its contribution to tau-mediated neurodegeneration.”

In the paper

“These results suggest that tau phosphorylation at Ser262 and Ser356 stabilizes less phosphorylated forms of tau (taulower) but does not promote tau phosphorylation at SP/TP sites (see also Fig 4).”

In the paper

“Thus, targeting multiple pools of abnormal tau stabilized by distinct pathways could additively suppress tau-mediated toxicity.”