Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

In the paper

“as the CAG repeats in polyglutamine-encoding RNAs can induce toxicity (74,75)”

What the sources say

• Supported

  The Abstract reports that interrupting CAG repeats within the polyglutamine-encoding region dramatically mitigated toxicity. It also reports that pathogenic-length CAG-repeat RNA induced neuronal degeneration even without encoding a toxic polyglutamine protein. No page number is supplied in our copy. (LLM, conf=0.93)

  cites [74] Li, 2008, RNA toxicity is a component of ataxin-3 degeneration in Drosophila, Nature source
• Disputed

  The Results section ('SCA8 CUGexp Not CAGexp Transcripts Misregulate GABT4') reports that CUG-expansion transcripts, but not CAG-expansion transcripts, altered GABT4 expression in the tested cells. The Introduction distinguishes the proposed toxic RNA effect of CUG transcripts from the polyglutamine protein encoded by CAG transcripts. This does not rule out every possible CAG-RNA toxicity, but the paper's finding runs contrary to the claim attributed to it. (LLM, conf=0.76)

  Checked by a reasoning model — may be wrong.

  cites [75] Daughters, 2009, RNA gain-of-function in spinocerebellar ataxia type 8, PLoS Genet. sourceExperimental — accuracy not yet measured

In the paper

“However, reduced ERK activity has also been shown to enhance tau-induced toxicity (132)”

What the sources say

• Disputed

  In “Tau Induces NMDAR-Dependent Activation of ERK1/2” (page not supplied), the paper reports that inhibiting ERK signaling or genetically removing ERK1 protects neurons from tau-induced cell death. It therefore finds the opposite of the attributed claim: reduced ERK activity lessens, rather than enhances, tau toxicity. (LLM, conf=0.93)

  Checked by a reasoning model — may be wrong.

  cites [132] Amadoro, 2006, NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, we also observe a strong decrease in GSK-3β activity in white and brown mutants and a strong increased activity in a rosy mutant (61).”

What the sources say

• Disputed

  The Results passage on GSK-3β activation and Figure 4B (page not provided in our copy) say the opposite for white and white-plus-brown flies: inhibitory Ser9 phosphorylation decreases, indicating increased GSK-3β activity. Figure 4B says a rosy mutation restores that inhibitory phosphorylation in this background, not that rosy increases activity. (LLM, conf=0.92)

  Checked by a reasoning model — may be wrong.

  cites [61] Ambegaokar, 2010, Interaction between eye pigment genes and tau-induced neurodegeneration in Drosophila melanogaster, Genetics sourceExperimental — accuracy not yet measured

In the paper

“The degree of roughness is intermediate and more pronounced in the anterior eye, making it useful for enhancer–suppressor modifier screens.”

What the sources say

• Supported

  The description of gl-tau eyes accompanying Figure 1 says they are rough in anterior regions while posterior regions appear normal; the methods describe a line with a moderate phenotype. Figures 2 and 5 show that genetic changes can both suppress and enhance the rough-eye phenotype, supporting its usefulness for modifier screens. (LLM, conf=0.85)

  cites [47] Jackson, 2002, Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila, Neuron source

In the paper

“Our laboratory generated a model of tauopathy in Drosophila melanogaster by expressing human wild-type full-length (2N/4R) tau in the eye using a direct fusion construct of the human tau cDNA to the eye-specific glass (gl) promoter (gl-tau fly). This misexpression causes a rough eye phenotype associated with abnormalities of photoreceptor neurons and other cell types in the underlying retina (47).”

What the sources say

• Supported

  The gl-tau model description (page unavailable in our copy) says the longest four-repeat human tau isoform was placed in a modified GMR eye-expression vector and that the flies developed a rough eye. Figure 1 reports disorganized retinal architecture, photoreceptor loss, and abnormalities involving other eye structures. The vector description supports direct eye-specific expression, although it names a modified GMR vector rather than simply a glass promoter. (LLM, conf=0.88)

  cites [47] Jackson, 2002, Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila, Neuron source

In the paper

“Additionally, Tom20 and Tom70 have been associated to Parkinson's disease-linked parkin and ALS-linked SOD1 (64,65).”

What the sources say

• Supported

  The paper identifies Parkin as Parkinson disease-related and reports that it mediates degradation of Tom20 and Tom70 (Abstract). This supports the Parkin association attributed to this source; the sentence's separate SOD1 association has another citation. (LLM, conf=0.91)

  cites [64] Yoshii, 2011, Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane, J. Biol. Chem source
• Partly supported

  The Results report increased TOM20 in spinal-cord mitochondria from rats expressing ALS-linked SOD1 G93A, supporting an association between TOM20 and mutant SOD1. The cited paper's passages identify TOM20, TOM22, and TOM40, but do not establish an association between TOM70 and SOD1. They also do not establish the parkin association, which may be the subject of the sentence's other citation. (LLM, conf=0.88)

  cites [65] Li, 2010, ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, tau phosphorylation at specific sites has been shown to ameliorate tau-induced deficits and toxicity (40)”

What the sources say

• Supported

  In “Phosphorylation of tau by MARK2,” the authors report that MARK2 greatly increases phosphorylation at tau’s KXGS motifs and that this correlates with rescue of tau-induced synapse decay. The Discussion further states that MARK2 prevents tau-induced damage and cannot rescue traffic defects when those sites are made nonphosphorylatable. The claim is supported in the context of the neuronal cultures studied. (LLM, conf=0.90)

  cites [40] Thies, 2007, Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1, J. Neurosci. source

In the paper

“This approach was used to validate the in vivo protective effects of PSA, with genetic loss-of-function (LOF) mutations in Drosophila PSA (dPSA) enhancing the tau phenotype and overexpression of dPSA suppressing the roughness (48).”

What the sources say

• Supported

  The Results report that a dPSA transposon insertion and a deletion of the PSA locus enhanced the tau rough-eye phenotype. They also report that dPSA overexpression suppressed the tau-induced eye phenotype (Results, Figures 4 and 6; page unavailable). (LLM, conf=0.93)

  cites [48] Karsten, 2006, A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration, Neuron source

In the paper

“Although associated with mitochondria, Tom34 is found more predominantly in the cytosol and binds to the chaperone proteins Hsp90 and Hsp70, as does Tom70 (66–68).”

What the sources say

• ?Not checked — no full text of the sourcecites [66] Yang, 2002, Yeast two-hybrid screening identifies binding partners of human Tom34 that have ATPase activity and form a complex with Tom34 in the cytosol, Arch. Biochem. Biophys. source
• Partly supported

  The Discussion (page unavailable) describes Tom34 as a suggested cytosolic protein and reports that it forms complexes with Hsp90. It does not establish that Tom34 is predominantly cytosolic or that it binds Hsp70. The paper discusses Tom70’s interaction with Hsp90, but its only mention connecting Tom70 to Hsp70 is the title of a cited work in the References. (LLM, conf=0.86)

  cites [67] Tsaytler, 2009, Novel Hsp90 partners discovered using complementary proteomic approaches, Cell Stress Chaperones sourceExperimental — accuracy not yet measured
• Partly supported

  The Tom70 Import Pathway section (page unavailable) says Tom70 interacts with Hsc70/Hsp70 and Hsp90. Our copy does not address Tom34’s localization or its binding to those chaperones (searched: Tom34 and predominantly cytosolic Tom34), so the Tom34 portion is unsupported. (LLM, conf=0.86)

  cites [68] Fan, 2011, Function of cytosolic chaperones in Tom70-mediated mitochondrial import, Protein Pept. Lett. sourceExperimental — accuracy not yet measured

In the paper

“Several invertebrate and vertebrate transgenic animal models have shown that tau can induce neurodegeneration and apoptosis (43–46).”

What the sources say

• ?Not checked — no full text of the sourcecites [43] Ishihara, 1999, Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform, Neuron source
• ?Not checked — no full text of the sourcecites [44] Lewis, 2000, Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein, Nat. Genet. source
• ?Not checked — no full text of the sourcecites [45] Wittmann, 2001, Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles, Science source
• Partly supported

  The Abstract reports age-dependent loss of axons and neurons in transgenic C. elegans expressing tau. The Discussion also describes neurodegeneration in Drosophila and mouse tau models. Neither passage establishes apoptosis, so that part of the claim is unsupported. (LLM, conf=0.87)

  cites [46] Kraemer, 2003, Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured

In the paper

“Most notably, Tomm40 has been reported in several publications to be a risk factor in AD (63).”

What the sources say

• Supported

  The section on TOMM40 variable-length polymorphism reports that TOMM40-region variants were associated with Alzheimer’s disease in published genome-wide association studies. It also describes a TOMM40 variant as contributing to disease risk, supporting the claim that TOMM40 has been reported as a risk factor. (LLM, conf=0.92)

  cites [63] Grossman, 2010, Alzheimer's disease: diagnostics, prognostics and the road to prevention, EPMA J. source

In the paper

“The gene csul interacts with histones, splicesosomal proteins and other small ribonucleoproteins and can affect protein–RNA affinity and intracellular localization of certain mRNAs (70–72).”

What the sources say

• Partly supported

  The JBP1 Immunoprecipitates Contain Protein Methyltransferase Activity section (page unavailable) shows that JBP1 methylates histones H2A and H4. The Discussion (page unavailable) mentions that arginine methylation facilitates export of certain hnRNPs, but does not establish that JBP1 affects protein–RNA affinity or mRNA localization. The cited passages do not establish interactions with spliceosomal proteins or other small ribonucleoproteins. (LLM, conf=0.84)

  cites [70] Pollack, 1999, The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [71] Anne, 2007, Arginine methyltransferase Capsuleen is essential for methylation of spliceosomal Sm proteins and germ cell formation in Drosophila, Development source
• Partly supported

  The Introduction identifies Csul as dPRMT5 and discusses methylation of spliceosomal Sm proteins and snRNP assembly. The section ‘sDMA modification of Aub affects PIWI-piRNA loading’ reports effects on Aub’s association with piRNAs and Aub’s localization in nurse cells. Our copy does not establish Csul interactions with histones or other small ribonucleoproteins, or an effect on the intracellular localization of mRNAs; the localization result concerns a protein. (LLM, conf=0.85)

  cites [72] Nishida, 2009, Functional involvement of Tudor and dPRMT5 in the piRNA processing pathway in Drosophila germlines, EMBO J. sourceExperimental — accuracy not yet measured

In the paper

“A recent report observed that mRNAs also associate with Tom70 (73), further establishing a link between RNA and RNA-associated proteins and tau toxicity.”

What the sources say

• Partly supported

  The Results report that deleting TOM70 significantly reduced the colocalization of ATP2 and OXA1 mRNAs with mitochondria. The Discussion interprets this as suggesting that TOM components may interact with different RNAs, but the paper does not report observing mRNAs associate directly with Tom70. (LLM, conf=0.85)

  cites [73] Gadir, 2011, Localization of mRNAs coding for mitochondrial proteins in the yeast Saccharomyces cerevisiae, RNA sourceExperimental — accuracy not yet measured

In the paper

“RNA regulation may also play a significant role in polyQ toxicity as well, as the CAG repeats in polyglutamine-encoding RNAs can induce toxicity (74,75), and polyglutamine proteins can also bind RNA with an affinity dependent on the polyQ expansion length (76).”

What the sources say

• Supported

  The supplied Abstract passages report that changing the CAG sequence while preserving the encoded polyglutamine protein mitigated toxicity, and that an untranslated CAG-repeat RNA caused neuronal degeneration. They support the cited point that CAG-repeat RNA can contribute to polyQ toxicity; the separate protein–RNA binding claim is attached to citation 76, not this source. (LLM, conf=0.94)

  cites [74] Li, 2008, RNA toxicity is a component of ataxin-3 degeneration in Drosophila, Nature source
• Partly supported

  The Discussion (page unavailable) reports that CUG-expansion RNA disrupts splicing regulation and plays a significant role in SCA8, a disorder that also produces a polyglutamine protein. It does not show that the CAG-repeat RNAs encoding that protein themselves induce toxicity, as the citing sentence suggests; the Discussion says the relative contributions of RNA and protein effects remain to be assessed. (LLM, conf=0.86)

  cites [75] Daughters, 2009, RNA gain-of-function in spinocerebellar ataxia type 8, PLoS Genet. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [76] Yue, 2001, The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract, Hum. Mol. Genet. source

In the paper

“Indeed, mature protein substrates of Tom70 were observed to be aggregate-prone in the absence of Tom70, suggesting a crucial role of Tom70 in preventing aggregation (69).”

What the sources say

• Supported

  The Discussion reports that the mature parts of Tom70-dependent precursors formed insoluble aggregates in a cell-free system and that the receptor domain of Tom70 suppressed this aggregation. This supports the citing sentence’s conclusion that Tom70 helps prevent aggregation, within the tested conditions. (LLM, conf=0.93)

  cites [69] Yamamoto, 2009, Roles of Tom70 in import of presequence-containing mitochondrial proteins, J. Biol. Chem. source

In the paper

“Mekk1 is a stress-induced MAP3K that leads to phosphorylation and activation of the stress-activated kinase, p38 MAPK (87).”

What the sources say

• Supported

  The paper identifies Drosophila D-MEKK1 as a MAPKKK whose activity rises under environmental stress (Abstract; Discussion). In the section on environmental stresses, inducing D-MEKK1 increased phosphorylated D-p38, and mutants showed reduced stress-induced D-p38 activation. (LLM, conf=0.90)

  cites [87] Inoue, 2001, A Drosophila MAPKKK, D-MEKK1, mediates stress responses through activation of p38 MAPK, EMBO J. source

In the paper

“The Aβ42 eye produces a very rough and small eye, with increased roughness and ommatidial fusion toward the posterior of the eye (Fig. 8C; 89).”

What the sources say

• Partly supported

  In “Generation of a new AD model in flies” and the Figure 1 caption (page not provided), the paper describes Aβ42-expressing eyes as small and highly disorganized, supporting the small, rough-eye description. It does not report increasing roughness or ommatidial fusion toward the posterior of the eye. (LLM, conf=0.86)

  cites [89] Casas-Tinto, 2011, The ER stress factor XBP1s prevents amyloid-beta neurotoxicity, Hum. Mol. Genet. sourceExperimental — accuracy not yet measured

In the paper

“GSK-3β has several downstream targets and is a regulator in many pathways, including Wnt, PI3K and Hedgehog signaling (104–106).”

What the sources say

• ?Not checked — no full text of the sourcecites [104] Cadigan, 2006, Wnt signaling: complexity at the surface, J. Cell Sci. source
• Partly supported

  The section on PKB in G1/S progression describes GSK-3β acting on cyclin D1 and c-Myc and being inhibited by PKB, supporting multiple targets and a role in PI3K/PKB signaling. The passages do not address a role for GSK-3β in Wnt or Hedgehog signaling (searched: Wnt, Hedgehog). Page numbers were not provided. (LLM, conf=0.88)

  cites [105] Liang, 2003, Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression, Cell Cycle sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [106] Wang, 2007, Shifting paradigms in Hedgehog signaling, Curr. Opin. Cell Biol. source

In the paper

“The data presented here agree with these previous reports and replicate a previous report from our laboratory that LOF of one copy of shaggy suppresses tau toxicity (47).”

What the sources say

• Supported

  The passage describing Figure 2A–B reports that the severe eye phenotype caused by two copies of the tau transgene was dramatically suppressed in flies heterozygous for a shaggy loss-of-function mutation. The Figure 2 caption likewise identifies this as suppression of the tau rough-eye phenotype. Page numbers are not supplied in our copy. (LLM, conf=0.93)

  cites [47] Jackson, 2002, Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila, Neuron source

In the paper

“GSK-3β, the mammalian homolog of sgg, is strongly implicated in AD (93)”

What the sources say

• Supported

  The Concluding remarks state that substantial data strongly implicate GSK3 in AD pathogenesis. The GSK3 and tau phosphorylation section specifically links GSK3β to tau pathology and neurodegeneration, and identifies shaggy as the Drosophila form of GSK3. No page numbers are available in our copy. (LLM, conf=0.91)

  cites [93] Hooper, 2008, The GSK3 hypothesis of Alzheimer's disease, J. Neurochem. source

In the paper

“Suppression of Aβ42 toxicity supports previous reports in cell, mouse and fly models in which Aβ42 induces GSK-3β activity and inhibition or reduction of GSK-3β ameliorates Aβ42-induced degeneration, either independent of or in concert with tau toxicity (99–101).”

What the sources say

• ?Not checked — no full text of the sourcecites [99] Folwell, 2009, Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease, Exp. Neurol. source
• Supported

  The Abstract (page unavailable) reports that Aβ42 expression increased GSK-3 activity in the adult-onset fly model and that genetic or lithium-mediated GSK-3 inhibition rescued Aβ42 toxicity. The Discussion (page unavailable) reports protection in the presence or absence of tau and cites related observations in cells and mice. (LLM, conf=0.87)

  cites [100] Sofola, 2010, Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease, PLoS Genet. source
• Partly supported

  Section 2.2 (β-Amyloid; page unavailable) reports that Aβ activates GSK-3β in hippocampal cultures and that inhibiting GSK-3β prevents Aβ-induced neuronal toxicity; it also describes protective effects of GSK-3 deactivation in mouse models. The copy does not establish these findings specifically for Aβ42 across cell, mouse, and fly models, and it does not report a fly model. (LLM, conf=0.86)

  cites [101] Lei, 2011, GSK-3 in neurodegenerative diseases, Int. J. Alz. Dis. sourceExperimental — accuracy not yet measured

In the paper

“TDP-43 can be phosphorylated, which is hypothesized to play a role in its toxicity (102,103).”

What the sources say

• Supported

  The Discussion says that phosphorylation of TDP-43 facilitates oligomer and filament formation and proposes that these structures may be neurotoxic. It explicitly describes abnormal phosphorylation as potentially pathological through toxic gain-of-function, matching the claim’s tentative wording. (LLM, conf=0.93)

  cites [102] Hasegawa, 2008, Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, Ann. Neurol. source
• Supported

  The Biochemistry of Pathological TDP-43 section reports that pathological TDP-43 is phosphorylated. The Genetics of Pathological TDP-43 section suggests that aberrant phosphorylation could play a role in disease onset or progression, supporting the citing sentence’s hedged claim about toxicity. (LLM, conf=0.87)

  cites [103] Geser, 2010, Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies, Neuropathology source

In the paper

“Additionally, in the process of conducting this screen, the background genes white, brown and rosy were also identified as modifiers (61), yielding a total of 40 modifier genes.”

What the sources say

• Partly supported

  The Abstract (page not supplied) reports that white, brown, and rosy affect the tau-induced eye phenotype, supporting their identification as modifiers. Our copy does not say they were identified during the cited screen or give a total of 40 modifier genes. (LLM, conf=0.86)

  cites [61] Ambegaokar, 2010, Interaction between eye pigment genes and tau-induced neurodegeneration in Drosophila melanogaster, Genetics sourceExperimental — accuracy not yet measured

In the paper

“Two modifiers identified in an unbiased manner from these screens, par-1 and shaggy, are known tau kinases (24,25,90–92)”

What the sources say

• ?Not checked — no full text of the sourcecites [24] Hanger, 1992, Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase, Neurosci. Lett. source
• ?Could not verify

  The Introduction and Results report that GSK3 phosphorylates tau, but our copy does not identify GSK3 as shaggy or discuss par-1 as a tau kinase. Searches for “shaggy,” “par-1,” and a Drosophila GSK3 homolog found no passage establishing either named modifier as a tau kinase. (LLM, conf=0.76)

  cites [25] Mandelkow, 1992, Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau, FEBS Lett. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [90] Drewes, 1995, Microtubule-associated protein/microtubule affinity-regulating kinase (p110MARK): a novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [91] Hernández, 2002, Spatial learning deficit in transgenic mice that conditionally over-express GSK-3βeta in the brain but do not form tau filaments, J. Neurochem. source
• ?Not checked — no full text of the sourcecites [92] Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source

In the paper

“GSK-3β has recently been shown to phosphorylate a key regulatory Ser in PAR-1; however, it remains unclear whether this activates (119) or inactivates PAR-1 (120,121).”

What the sources say

• Supported

  The Discussion identifies Ser-212 in MARK2/PAR-1’s activation loop as the site GSK-3β phosphorylates. In the section on Ser-212 and kinase activity (page unavailable), the authors say their findings suggest activation but acknowledge contrary evidence that Ser-212 phosphorylation is inhibitory. This supports the citing sentence’s phosphorylation claim and its stated uncertainty; citation 119 is attached to the activation possibility. (LLM, conf=0.90)

  cites [119] Kosuga, 2005, GSK-3βeta directly phosphorylates and activates MARK2/PAR-1, J. Biol. Chem. source
• Supported

  This citation is attached to the possibility that phosphorylation inactivates PAR-1. In “Control of MARK2 by phosphorylation of the activation loop” (page unavailable), the paper says phosphorylation of the regulatory S212 in MARK2/PAR-1 appears inhibitory. (LLM, conf=0.90)

  cites [120] Timm, 2003, MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1, EMBO J. source
• Supported

  The citation to this paper is attached to the possibility that GSK-3β inactivates PAR-1. The Discussion states that GSK-3β phosphorylates MARK2/Par-1 at Ser-212 and that this produces an inactive kinase; it also acknowledges a contrasting report of activation. The paper itself concludes inactivation, rather than leaving its own result unresolved. (LLM, conf=0.91)

  cites [121] Timm, 2008, Glycogen synthase kinase (GSK) 3β directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2, J. Biol. Chem. source

In the paper

“LKB-1 phosphorylates and activates PAR-1 (120,122,123), but also phosphorylates the inactivating Ser-9 on GSK-3β and may be the elusive GSK-3β kinase activated by Wnt signaling (124).”

What the sources say

• ?Could not verify

  This source is cited for the PAR-1 activation clause, not the separately cited GSK-3β clause. The Introduction identifies MARKK as a kinase that phosphorylates and activates MARK/PAR-1, but neither it nor the passages retrieved for LKB-1 say that LKB-1 does so. The copy does not rule out LKB-1 as another activating kinase. (LLM, conf=0.76)

  cites [120] Timm, 2003, MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1, EMBO J. sourceExperimental — accuracy not yet measured
• ?Could not verify

  Citation (124) is attached to the GSK-3β clause. The paper’s ‘Phosphorylation and activation of the MARK kinases by LKB1’ section reports phosphorylation of MARK kinases, but no passage found for GSK-3β Ser-9 phosphorylation or an LKB1 kinase role activated by Wnt signaling (searched: GSK3, Ser-9, and Wnt signaling). (LLM, conf=0.75)

  cites [122] Lizcano, 2004, LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1, EMBO J. sourceExperimental — accuracy not yet measured
• Supported

  This source is cited for the PAR-1 clause (citations 120, 122, 123), not the GSK-3β clause (citation 124). The section “LKB1 phosphorylates PAR-1 T408 site in vitro and in vivo” reports direct phosphorylation, and the Introduction identifies LKB1 as an activating kinase of PAR-1. (LLM, conf=0.94)

  cites [123] Wang, 2007, Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1, J. Neurosci. source
• Partly supported

  In “Kinases at the Center and Poles of the Action” (page not available), the paper says Lkb1 regulates inhibitory Ser-9 phosphorylation of GSK-3β, but does not say Lkb1 directly phosphorylates that site. It also says Ser-9 phosphorylation is not a step in Wnt signal transduction, so it does not support identifying Lkb1 as a GSK-3β kinase activated by Wnt. The PAR-1 clause has separate citations and is not assessed here. (LLM, conf=0.88)

  cites [124] Green, 2004, Lkb1 and GSK3-beta: kinases at the center and poles of the action, Cell Cycle sourceExperimental — accuracy not yet measured

In the paper

“Both Nishimura et al. (92) and Chatterjee et al. (42) reported that increased par-1 expression increases tau toxicity”

What the sources say

• ?Not checked — no full text of the sourcecites [92] Nishimura, 2004, PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila, Cell source
• Supported

  In the Results section on PAR-1-induced phosphorylation (Fig. 4), coexpression of PAR-1 made the rough-eye phenotype and retinal abnormalities caused by wild-type tau more severe. The authors caution that the combined effect may be additive rather than synergistic, but the citing claim does not assert synergy. (LLM, conf=0.92)

  cites [42] Chatterjee, 2009, Dissociation of tau toxicity and phosphorylation: role of GSK-3βeta, MARK and Cdk5 in a Drosophila model, Hum. Mol. Genet. source

In the paper

“Apart from its effects on microtubule binding, phosphorylation can alter tau subcellular localization to dendritic spines (127) or can alter its affinity for the plasma membrane (128), thereby causing alterations in synaptic function (127,129).”

What the sources say

• Supported

  The Results section (“Role of phosphorylation in htau mislocalization”) states that tau mislocalization to dendritic spines and subsequent synaptic dysfunction depend on tau phosphorylation. The plasma-membrane-affinity clause is cited to reference 128, not this source. (LLM, conf=0.94)

  cites [127] Hoover, 2010, Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration, Neuron source
• ?Not checked — no full text of the sourcecites [128] Pooler, 2011, Dynamic association of tau with neuronal membranes is regulated by phosphorylation, Neurobiol. Aging source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [129] Ittner, 2010, Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models, Cell source

In the paper

“ERK can phosphorylate tau (29), and elevated activity of MAPK/ERK has been reported in several tauopathies and may play a role in early stages of neurofibriliary tangle (NFT) formation (82,130,131).”

What the sources say

• Supported

  Citation (29) is attached only to the claim that ERK can phosphorylate tau; the later claims have separate citations. The Abstract identifies the tau-phosphorylating 42 kDa kinase as a MAP kinase and states that it phosphorylates tau. No page number is supplied for the Abstract. (LLM, conf=0.90)

  cites [29] Drewes, 1992, Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state, EMBO J. source
• Partly supported

  The Abstract reports increased phosphorylated MAPK/ERK in argyrophilic grain disease and its presence in neurons with pre-tangles, supporting an association with early tangle formation. The paper's own findings are limited to that disease; its reference list names research on other tauopathies, but does not itself establish elevated MAPK/ERK activity across several tauopathies. (LLM, conf=0.84)

  cites [82] Ferrer, 2003, Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease, Brain Pathol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [130] Pei, 2002, Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease, Brain Res. Mol. Brain Res. source
• Supported

  The Abstract reports markedly increased phosphorylated (active) ERK in Alzheimer disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. It also associates active ERK with early tau deposition and notes less frequent staining in neurons with developed tangles, supporting the hedged claim about early NFT formation. The separate statement that ERK can phosphorylate tau is attached to citation (29), not this source. (LLM, conf=0.93)

  cites [131] Ferrer, 2001, Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration, Brain Pathol. source

In the paper

“AKT phosphorylates and enhances PAR-1 activity (125).”

What the sources say

• Partly supported

  The Results report that Akt binds PAR1/MARK2 and increases PAR1-associated phosphorylation of tau; the Discussion describes possible regulation of PAR1/MARK2 activity. Neither section shows that Akt phosphorylates PAR1 itself, and the Results leave open whether Akt activates PAR1 or instead makes tau more accessible to it (page numbers unavailable). (LLM, conf=0.88)

  cites [125] Dickey, 2008, Akt and CHIP coregulate tau degradation through coordinated interactions, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured

In the paper

“Two modifiers of tau toxicity—Atg6 and Dlic2 (dynein light chain 2)—were also recently identified as modifiers of lysosomal/autophagic vacuole trafficking (193)”

What the sources say

• Supported

  The paper identifies Atg6 mutations as enhancers of the Blue Cheese eye phenotype in “Modifying autophagy genes” (page unavailable). In “Lysosomal-autophagic trafficking defects” (page unavailable), it lists dlic2 as a dynein light-chain modifier and discusses dynein light-chain mutations among trafficking-related modifiers. The cited finding concerns the Blue Cheese phenotype; the sentence does not attribute the tau-toxicity finding to this source. (LLM, conf=0.88)

  cites [193] Simonsen, 2007, Genetic modifiers of the Drosophila blue cheese gene link defects in lysosomal transport with decreased life span and altered ubiquitinated-protein profiles, Genetics source

In the paper

“It is interesting to note that both KSR and NRG (137–139) are involved in scaffolding membrane-associated proteins”

What the sources say

• ?Not checked — no full text of the sourcecites [137] Whittard, 2006, MAP kinase pathway-dependent phosphorylation of the L1-CAM ankyrin binding site regulates neuronal growth, Mol. Biol. Cell source
• Supported

  The discussion (p. 653) says neuroglian recruits ankyrin to the plasma membrane, where ankyrin provides an attachment site for spectrin and other membrane-skeleton proteins. This supports the NRG portion of the claim for which this paper is cited. (LLM, conf=0.88)

  cites [138] Dubreuil, 1996, Neuroglian-mediated cell adhesion induces assembly of the membrane skeleton at cell contact sites, J. Cell Biol. source
• ?Not checked — no full text of the sourcecites [139] Bennett, 1999, Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels, J. Neurocytol. source

In the paper

“previous efforts have suggested that tau toxicity may be partially due to ‘hyperstabilization’ of microtubules (42)”

What the sources say

• Supported

  The Discussion section says that tau may bind irreversibly to microtubules, overstabilizing them and blocking transport-dependent cellular processes. It identifies this as a possible form of tau pathology, matching the citing sentence’s qualified claim. No page number is provided in the supplied passages. (LLM, conf=0.93)

  cites [42] Chatterjee, 2009, Dissociation of tau toxicity and phosphorylation: role of GSK-3βeta, MARK and Cdk5 in a Drosophila model, Hum. Mol. Genet. source

In the paper

“Mekk1 is a MAP3K that leads to the phosphorylation and activation of p38/MAPK (87), which is activated in response to cell stress (142–144).”

What the sources say

• Supported

  The “D-MEKK1 is a MAPKKK” section reports that D-MEKK1 activates the MKK6–p38 pathway. The “Environmental stresses activate the D-MEKK1–D-p38 pathway” section also reports increased phosphorylated D-p38 after D-MEKK1 induction. Citation (87) is attached to this phosphorylation-and-activation claim; the stress-response clause has separate citations. (LLM, conf=0.94)

  cites [87] Inoue, 2001, A Drosophila MAPKKK, D-MEKK1, mediates stress responses through activation of p38 MAPK, EMBO J. source
• Partly supported

  The Introduction identifies Drosophila Mekk1 as a MAPKKK and reports reduced p38 activation in Mekk1 mutants; the Discussion likewise says Mekk1 inhibition reduces p38 activation. Our copy does not specifically state that Mekk1 leads to p38 phosphorylation. The cell-stress clause has separate citations in the citing sentence, so it is not assessed against this source. (LLM, conf=0.84)

  cites [142] Brun, 2006, The MAPKKK Mekk1 regulates the expression of Turandot stress genes in response to septic injury in Drosophila, Genes Cells sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [143] Sano, 2005, Drosophila activating transcription factor-2 is involved in stress response via activation by p38, but not c-Jun NH(2)-terminal kinase, Mol. Biol. Cell. source
• ?Not checked — no full text of the sourcecites [144] Zhuang, 2006, Regulation of Drosophila p38 activation by specific MAP2 kinase and MAP3 kinase in response to different stimuli, Cell Signal. source

In the paper

“both of which promote ERK signaling (133–136)”

What the sources say

• Partly supported

  The Discussion (page not provided) says KSR accelerates MEK and MAPK activation, supporting the KSR part of the claim. Our copy does not address whether Neuroglian (Nrg) promotes ERK signaling, so this source does not support that part. (LLM, conf=0.86)

  cites [133] Therrien, 1996, KSR modulates signal propagation within the MAPK cascade, Gen. Dev. sourceExperimental — accuracy not yet measured
• Supported

  The Abstract reports that KSR promotes signal propagation through the ERK/MAPK module, and the Discussion says it is required for transmission through that pathway. This supports the KSR part of the statement; the paper is not offered as evidence for Neuroglian specifically within the citation group. (LLM, conf=0.90)

  cites [134] Roy, 2002, KSR is a scaffold required for activation of the ERK/MAPK module, Gen. Dev. source
• ?Could not verify

  The passage labeled Abstract (page unavailable) describes Neuroglian acting through the FGF and EGF receptors during axon guidance, and separately says that L1 can signal through the MAP kinase pathway. It does not establish that Neuroglian promotes ERK signaling. A search for ksr and ERK signaling found no passage addressing ksr’s role either. (LLM, conf=0.72)

  cites [135] García-Alonso, 2000, The EGF and FGF receptors mediate neuroglian function to control growth cone decisions during sensory axon guidance in Drosophila, Neuron sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that Neuroglian functions through EGFR, and the Discussion links L1-type proteins to activation of the neuronal MAPK pathway. The paper does not establish that Neuroglian specifically promotes ERK signaling, and the passages found do not address ksr (searched: ksr, ERK, and MAPK). (LLM, conf=0.80)

  cites [136] Islam, 2004, Activation of EGF receptor kinase by L1-mediated homophilic cell interactions, Mol. Biol. Cell sourceExperimental — accuracy not yet measured

In the paper

“Elevated p38 activity is found in brains from patients with tauopathies (145–147) and in transgenic AD mice models expressing human tau (148–150) or mutant APP (151), both of which correlate with tau aggregation.”

What the sources say

• ?Not checked — no full text of the sourcecites [145] Hensley, 1999, p38 kinase is activated in the Alzheimer's disease brain, J. Neurochem. source
• ?Not checked — no full text of the sourcecites [146] Ferrer, 2003, Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation, Neuropathol. Appl. Neurobiol. source
• ?Not checked — no full text of the sourcecites [147] Hartzler, 2002, The p38 pathway is activated in Pick disease and progressive supranuclear palsy: a mechanistic link between mitogenic pathways, oxidative stress, and tau, Neurobiol. Aging source
• ?Not checked — no full text of the sourcecites [148] Sahara, 2004, Phosphorylated p38MAPK specific antibodies cross-react with sarkosyl-insoluble hyperphosphorylated tau proteins, J. Neurochem. source
• ?Not checked — no full text of the sourcecites [149] Kelleher, 2007, Kinase activities increase during the development of tauopathy in htau mice, J. Neurochem. source
• Partly supported

  The Materials and Methods identify the 3xTg-AD mice as expressing mutant human APP. The Results report increased activated p38 and tau aggregation in these mice after chronic nicotine treatment, but do not establish elevated p38 as a general finding in mutant-APP mice without that treatment. (LLM, conf=0.86)

  cites [150] Oddo, 2005, Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [151] Hwang, 2004, Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw, Exp. Neurol. source

In the paper

“LOF alleles of VCP/ter94 in Drosophila suppress polyglutamine toxicity (298) and retinal degeneration (299), similar to our finding of LOF of smid suppressing tau toxicity.”

What the sources say

• ?Not checked — no full text of the sourcecites [298] Higashiyama, 2002, Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration, Cell Death Differ. source
• Supported

  The citation to this paper (299) is attached to the retinal-degeneration part of the sentence, not the polyglutamine-toxicity part (298). The Results, in “Suppression of Rh1P37H-Induced Retinal Degeneration by VCP Loss-of-Function Alleles” (Figure 5), report that decreasing VCP function suppresses retinal degeneration in Rh1P37H flies. (LLM, conf=0.93)

  cites [299] Griciuc, 2010, Inactivation of VCP/ter94 suppresses retinal pathology caused by misfolded rhodopsin in Drosophila, PLoS Genet. source

In the paper

“Indeed, calpain A has been shown to cleave tau and is reported to be responsible for producing a 17 kDa fragment that may be a highly toxic tau derivative (211,212).”

What the sources say

• Supported

  The Introduction reports that calpain-1 activation generated a 17 kDa tau fragment in hippocampal neurons and that expression of the fragment led to neurite degeneration and cell death. The in vitro cleavage section also reports that calpain-1 cleaved full-length tau to produce a roughly 17 kDa fragment. (LLM, conf=0.91)

  cites [211] Park, 2005, The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration, J. Neurosci. source
• Partly supported

  The section 'Identification of the proteases responsible for producing the 17 kDa fragment' reports that purified calpain cleaves tau to produce a 17 kDa band matching the one seen during neuronal apoptosis (page not indexed). Our copy does not identify the protease specifically as 'calpain A' or describe the fragment as highly toxic; the Discussion instead suggests a possible role for tau cleavage in cytoskeletal breakdown. (LLM, conf=0.88)

  cites [212] Canu, 1998, Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis, J. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“Tau has the capacity to bind DNA (281,304) and may protect it from oxidative damage (305).”

What the sources say

• ?Not checked — no full text of the sourcecites [281] Hua, 2002, Effect of phosphorylation and aggregation on tau binding to DNA, Protein Pept. Lett. source
• ?Not checked — no full text of the sourcecites [304] Krylova, 2005, Tau protein binds single-stranded DNA sequence specifically—the proof obtained in vitro with non-equilibrium capillary electrophoresis of equilibrium mixtures, FEBS Lett. source
• Supported

  The Results section reports that DNA damage from hydroxyl free radicals decreased in the presence of tau in an in vitro experiment. The Discussion interprets this as protection from radical attack while noting that protection in vivo remains untested; the citing sentence’s “may protect” is consistent with that limitation. (LLM, conf=0.93)

  cites [305] Wei, 2008, Binding to the minor groove of the double-strand, tau protein prevents DNA from damage by peroxidation, PloS ONE source

In the paper

“Of these, 19 were putative modifiers.”

• Also stated in: § P lethal screen reveals 23 modifiers and EY screen reveals 14 modifiers · plain

  “they were included as tau modifiers making for a total of 14 EY modifiers.”

In the paper

“Additionally, the ERK signaling pathway appears to be relevant, with ksr and Nrg identified in the screen, but other signaling pathways were also predicted to be relevant, including the BMP/TGF-β, epidermal growth factor (EGF) and Hedgehog/Smoothened pathways”

In the paper

“however, csul overexpression increases Q108 toxicity, as evidenced by a smaller and more collapsed eye and increased pigmentation abnormalities.”

In the paper

“However, both genes also modify polyglutamine toxicity.”

In the paper

“Overxpression of Tom34 suppresses Q108 toxicity, as evidenced by reduced ommatidial fusion and increased pigment retention”

In the paper

“However, autophagy/lysosomal genes and genes related to RNA processing were also surprisingly highly represented, along with protein translation or ribosomal-associated genes.”

In the paper

“As expected, kinases and phosphatases occupy the largest functional group, and motor or cytoskeletal genes show a high degree of connectivity to many genes in the network.”

In the paper

“No hits from the P lethal screened showed any robust effect on the Q108 phenotype; similarly, almost none of the modifiers from the EY screen was appreciably different from the control (Fig. 2).”

In the paper

“The kinase shaggy/GSK-3β is one of the most highly connected genes in the network and is regulated by several pathways, including PI3K and Wnt, although no other Wnt pathway components were identified functionally or computationally.”

In the paper

“suppressors show consistently higher volumes than control samples, whereas enhancers show consistently lower volumes.”

In the paper

“The PI3K is the largest represented and the most highly connected signaling pathway in the network.”

In the paper

“These alleles neither appear to mitigate general apoptosis (assayed with GMR-hid) nor have any intrinsic effects on eye morphology (assayed with GMR-GAL4 alone).”

In the paper

“Using both GOF and LOF approaches, we observed that both Tom 34 and csul suppress tau toxicity when overexpressed and enhance toxicity when expression is reduced.”

In the paper

“Thirty-two of the 37 hits were annotated with a described function.”

In the paper

“Suppressors and enhancers of the gl-tau eye phenotype show strong changes in morphological eye volume, which can be used as a quantitative metric of modification.”

In the paper

“However, sgg and par-1 mutations did not show any significant effect on AT8 levels in trans to gl-tau, whereas CamKI and Mekk1, both enhancers, showed significant decreases in AT8 levels.”

In the paper

“The other half (22 of 40) showed a significant difference in AT8; however, no pattern of phosphorylation correlated with enhancement or suppression of the tau phenotype.”

In the paper

“Both enhancer bancal and suppressor ksr decrease ERK activity, but ksr also strongly reduced GSK-3β activity, while bancal trended to increase GSK-3β activity.”

In the paper

“Six modifiers showed a significant decrease in phosphorylation: three were enhancers (bl, Hop and Tango5) and three were suppressors (ksr, l(3)j11B2 and l(3)L1243).”

In the paper

“Only l(3)L6332 showed a significant increase in tau expression but suppressed toxicity; thus, its modifying effect is not attributable to any effect on tau expression.”

In the paper

“However, no other genes that are directly involved with RNA and protein localization or transport were screened, which suggests a specific role of RNA trafficking or localization in polyQ toxicity.”

In the paper

“Overexpression of Mekk1 also strongly reduced S202/T205 tau phosphorylation levels (AT8), but did not alter total tau levels (T46).”

In the paper

“As expected, both ksr and bancal showed significantly decreased phospho-ERK levels, indicating reduced ERK activity (Fig. 7B).”

In the paper

“38 of the 40 showed no effect on polyglutamine toxicity, with NC2α and SdhB being the only two exceptions (Fig. 9).”

In the paper

“this report is the first to demonstrate that mutant TDP-43 expression strongly induces GSK-3β activity (Fig. 8D) and that reduction in GSK-3β/shaggy can suppress TDP-43 toxicity (Fig. 8C).”

In the paper

“The TDP-43 phenotype is more subtle, with no obvious ommatidial fusion or roughness, but with characteristic discoloration to a darker brown-like color, and loss of pigmentation, starting in the periphery of the eye and leading to a mosaic-like pattern with aging (Fig. 8C).”

In the paper

“We were intrigued by the result that both ksr and bancal showed significant reductions in pS202/T205 (AT8) levels, although ksr is a strong suppressor, whereas bancal is a strong enhancer.”

In the paper

“Moreover, neither sgg nor par-1 loss of one copy produced any change in AT8 signal (Fig. 6).”

In the paper

“the opposing effects on tau toxicity exerted by reductions in par-1, an enhancer, and sgg, a suppressor”

In the paper

“Both enhancer bancal and suppressor ksr decrease ERK activity, but ksr also strongly reduced GSK-3β activity, while bancal trended to increase GSK-3β activity.”

In the paper

“Although NC2α and SdhB suppressed tau and polyglutamine toxicity, neither gene had a significant effect on the Aβ42 or the TDP-43Q331K phenotype.”

In the paper

“the modifiers Mekk1 and CamKI, both kinases that enhance tau toxicity despite producing reductions in AT8 levels (phospho-tau at S202/T205).”

In the paper

“We were intrigued by the result that both ksr and bancal showed significant reductions in pS202/T205 (AT8) levels, although ksr is a strong suppressor, whereas bancal is a strong enhancer.”

In the paper

“The suppressor ksr also showed moderate suppression of the Aβ42 phenotype, but not as robust as seen with sgg.”

In the paper

“When assayed for pGSK-3β[Ser9] (inactivated GSK-3β), we did indeed see a reduction of inactivated GSK-3β in bancal mutants when compared with control, although the result was not statistically significant (Fig. 7B).”

In the paper

“the S2A mutant tau construct, with only two residues (S262 and S356) made resistant to phosphorylation, exhibits no toxicity at all in the eye and furthermore cannot be rendered toxic by genetic enhancers of wild-type tau toxicity (Fig. 8B).”

In the paper

“Neither Mekk1 expression nor tau expression alone affects ERK activity, whereas co-expression leads to marked reduction of phospho-ERK levels (Fig. 6).”

In the paper

“Both are involved in the ERK pathway and, as expected, both bancal and ksr showed significantly reduced levels of pERK (Fig. 7B), which correlates well with the reduced AT8 levels seen with both genes.”

In the paper

“However, ksr showed a significantly higher level of inactivated GSK-3β, whereas bancal trended to lower levels of inactivated GSK-3β (Fig. 7B).”

In the paper

“Overexpression of Mekk1 was found to strongly enhance tau toxicity in this screen (Fig. 3) and increases p38 activity in our model (Fig. 6).”

In the paper

“Two genes—bancal and ksr—intrigued us as they showed similar reductions in AT8 levels (Fig. 6) but had opposite effects on toxicity.”

In the paper

“at S202/T205 (AT8 epitope), S262/S356 (12E8 epitope) or T181 (AT270 epitope) did not correlate with toxicity”

In the paper

“Smid is predicted to be a serine-type endopeptidase, although no substrates have been identified, and total tau protein levels and AT8 signal show no differences in trans to smid when compared with control, indicating that tau is not a substrate.”

In the paper

“We observe that tau functions synergistically with Mekk1 and p38 to down-regulate ERK activity, with a corresponding decrease in AT8-positive phosphorylation.”

In the paper

“The screen described here also differs from previously reported screens in that (i) tau expression and the phenotype of gl-tau eye are not GAL4-dependent, thus eliminating potential confounds of modifiers of GAL4 function and not tau toxicity”

In the paper

“Our screen was selective for dominant effects/haploinsufficiency and for essential genes in the case of the P lethal screen.”

In the paper

“Our screen was carried out with blinded phenotypic scoring, as P lethal lines were initially known only by their stock numbers; only after the F1 phenotypes were scored for modifying effect on the tau eye phenotype was information on P element location and the affected gene obtained.”

In the paper

“This may simply indicate that the eye and retina may not be the ideal tissue to induce or observe effects of these genes on tau toxicity.”

In the paper

“However, no other genes that are directly involved with RNA and protein localization or transport were screened, which suggests a specific role of RNA trafficking or localization in polyQ toxicity.”

In the paper

“The p38 pathway has been reported to interfere with ERK activity during apoptosis (see 88 for review); thus, ERK activity was assayed in these genotypes by measuring phospho-ERK levels.”

What the sources say

• ?Not checked — no full text of the sourcecites [88] Junttila, 2008, Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival, FASEB J. source

In the paper

“and polyglutamine proteins can also bind RNA with an affinity dependent on the polyQ expansion length (76).”

What the sources say

• ?Not checked — no full text of the sourcecites [76] Yue, 2001, The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract, Hum. Mol. Genet. source

In the paper

“Other genetic screens of polyQ toxicity have also uncovered RNA-binding proteins (77–79), although those genes identified do not overlap with the modifiers presented in this study.”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Fernandez-Funez, 2000, Identification of genes that modify ataxin-1-induced neurodegeneration, Nature source
• ?Not checked — no full text of the sourcecites [78] Mutsuddi, 2004, The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila, Curr. Biol. source
• ?Not checked — no full text of the sourcecites [79] Murata, 2008, RNA-binding protein hoip accelerates polyQ-induced neurodegeneration in Drosophila, Biosci. Biotechnol. Biochem. source

In the paper

“This result helps to explain that the sgg mutation might suppress toxicity by reducing levels of Sgg/GSK-3β and that ksr might exert its suppressive effects by increasing inactivated GSK-3β, as observed in gl-tau flies (Fig. 7B).”

In the paper

“These collections allowed for an unbiased, genome-spanning, blinded genetic screen.”