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PreprintCited by 0Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAlzheimer's disease research and treatments

Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis

Open access
Khan, Mohammed Repon, Yin, Xiling, Kang, Sung-Ung, Mitra, Jaba, Wang, Hu, Brahmachari, Saurav, Karuppagounder, Senthilkumar S., Kimura, Yasuyoshi +9 more·2022·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2022.10.03.510455
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Abstract

Pathologic α-syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD. Pathological α-synuclein (α-syn) plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic α-syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the α-syn preformed fibril (PFF) and Drosophila α-syn transgenic models of pathologic α-syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic α-syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.

AI snapshot

Written from the paper’s full text.

TL;DR

Pathologic α-synuclein binds TSC2, destabilizes the TSC1-TSC2 complex, activates mTORC1, and enhances mRNA translation, contributing to neurodegeneration in Parkinson’s disease models. Genetic and pharmacologic inhibition of mTORC1 or translation rescues dopamine neuron loss, behavioral deficits, and α-syn pathology in α-syn PFF mouse and Drosophila models.

Key findings

  • Proteomics identified 2,015 A53T α-syn-APEX interactors in HEK293 cells and 932 α-syn PFF interactors in mouse striatum, with 256 proteins common to both datasets; translation and mTOR pathways were statistically enriched.
  • Pathologic α-syn PFF increased protein translation in cell-free IVT, Drosophila S35 pulse labeling, polysome profiling, and neuronal SUnSET assays, while monomeric WT and A53T α-syn repressed translation.
  • SiMPull showed 0.5 nM α-syn PFF dissociated 50% of the TSC1-TSC2 complex; mTORC1 remained stable even at 5,000 nM α-syn PFF, and Aβ oligomers or Tau PFF did not disassemble TSC1-TSC2.
  • Rapamycin reduced P-S129 α-syn, S6K/4E-BP1 phosphorylation, TH/Nissl neuron loss, and behavioral deficits in intrastriatal α-syn PFF mice; S6K inhibitor, anisomycin, 4E-BP1 overexpression, and TSC2 overexpression rescued fly and primary neuron phenotypes. Human PD cingulate cortex showed increased 4E-BP1 phosphorylation, and substantia nigra, cingulate, and inferior parietal cortex showed reduced TSC1-TSC2 levels.

Methods

  • Proteomic interaction mapping used A53T α-syn-APEX labeling in HEK293 cells and biotinylated α-syn PFF pulldown from mouse striatum followed by mass spectrometry.
  • Translation was measured by cell-free in vitro translation, SUnSET in primary cortical neurons, S35 radioactive pulse labeling in Drosophila, and polysome profiling; TSC1-TSC2 and mTORC1 complex stability was assessed by single-molecule pulldown (SiMPull).
  • Models included Drosophila α-syn transgenic lines (TH-Gal4, Elav-Gal4, Syb-QF2) and intrastriatal α-syn PFF-injected C57BL/6J mice; rapamycin was given at 6 mg/kg intraperitoneally or as microencapsulated rapamycin in diet, and fly drugs included 0.5 µM rapamycin, 10 µM PF-4708671, and 10 µM anisomycin. Statistical analyses used unpaired two-tailed t-tests and one-way ANOVA where reported.

Limitations

  • The paper does not include a dedicated limitations section.
  • Evident from the text: human evidence is postmortem and cross-sectional, so it cannot establish causal direction between TSC1-TSC2 loss, mTORC1 activation, and PD pathogenesis.
  • Evident from the text: neuroprotection and mechanistic rescue data come from Drosophila, primary cortical neurons, and α-syn PFF mouse models, not from human therapeutic trials; some interaction data rely on overexpressed or cell-free systems.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1101/2022.10.03.510455

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

20 of 25 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Pathologic a-syn can lead to defects in protein homeostasis.

    “Pathologic a-syn can lead to defects in protein homeostasis (4).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] D. L. Manecka , B. Vanderperre , E. A. Fon , T. M. Durcan , The Neuroprotective Role of Protein Quality Control in Halting the Development of Alpha-Synuclein Pathology. Front Mol Neurosci 10, 311 (2017). source
  • Premisecitation

    mTORC1 and 4E-BP1 play important role in mitochondrial health.

    “Since mTORC1 and 4E-BP1 play important role in mitochondrial health (26,27), mitochondrial morphology using Transmission Electron Microscopy (TEM) was examined.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [26] source
    • cites [27] source
  • Premisecitation

    The Drosophila Syb-QF2> a-syn model exhibits robust pathologic a-syn induced degeneration.

    “The Drosophila Syb-QF2> a-syn model, which exhibits robust pathologic a-syn induced degeneration (16), showed a significant increase in P-S129 a-syn and d4EBP phosphorylation that was reduced by feeding the flies, the mTOR inhibitor, rapamycin (Figures 3C and3D).”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    Activation of 4E-BP1 by rapamycin treatment is sufficient to rescue dopamine neuron loss and motor deficits in Drosophila PINK1 and parkin models.

    “Moreover, activation of 4E-BP1 by rapamycin treatment is sufficient to rescue dopamine neuron loss and motor deficits in Drosophila PINK1 and parkin models of DA neuron loss (7).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Premisecitation

    S6K phosphorylation by mTOR is linked to translation activation.

    “Since S6K phosphorylation by mTOR is linked to translation activation (19), we explored the possibility of whether specific inhibition of S6K could rescue PD pathology and neurodegeneration in the pathologic α-syn model (Syb-QF2> α-syn) (16).”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 11
  • The quote only partly states this claim. 3

  • May combine two claims.

    Premisecitation

    Activated mTOR phosphorylates 4E-BP1, leading to inhibition of 4E-BP1's repression of 5'cap-dependent translation and initiation of 5'cap-dependent translation.

    “Activated mTOR phosphorylates 4E-BP1, which leads to inhibition of 4E-BP1's repression of 5'capdependent translation resulting in the initiation of 5'cap-dependent translation (23,24).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [23] source
    • cites [24] source

      The Abstract explains that 4E-BP1 inhibits cap-dependent translation and that its hyperphosphorylation prevents binding to eIF4E, relieving that inhibition. It also says mTOR signaling is required for 4E-BP1’s release from eIF4E. But the Discussion states that the kinase responsible for phosphorylating 4E-BP1 in vivo is unknown, so the claim that activated mTOR directly phosphorylates it is stronger than the paper supports. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    4E-BP1 overexpression provides neuroprotection against misfolded protein stress and a-syn mediated neurodegeneration.

    “Consistent with our findings, prior studies have shown that 4E-BP1 overexpression provides neuroprotection against misfolded protein stress and a-syn mediated neurodegeneration (26).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Defects in mRNA translation are linked to autosomal dominant PD and autosomal recessive PD, where there is aberrant bulk protein synthesis coupled to neurodegeneration.

    “Defects in mRNA translation are linked to autosomal dominant PD (5,6) and autosomal recessive PD (7), where there is aberrant bulk protein synthesis that is coupled to neurodegeneration (8,9).”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [5] source
    • cites [6] source

      The Introduction (page not available in our copy) links dominant LRRK2-mutant PD to dysregulated translation and reports increased global protein synthesis coupled to neurotoxicity in Drosophila models. The paper does not establish the corresponding claim for autosomal recessive PD; its human-neuron findings concern altered translation of particular mRNAs rather than a demonstrated change in bulk protein synthesis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [7] source

      The Results sections on 4E-BP activity and neuron loss (page unavailable) link altered translation regulation in recessive parkin/PINK1 fly mutants to dopaminergic neurodegeneration: the pathway regulating global translation is down-regulated, and increasing 4E-BP protects neurons. The paper does not establish aberrant bulk protein synthesis itself as coupled to neurodegeneration; it assesses translation-regulatory activity, and describes the existing down-regulation as a protective stress response. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [8] 2016, Decoding Parkinson’s Disease Pathogenesis: The Role of Deregulated mRNA Translation, J Parkinsons Dis source

      The ‘Deregulated Translation in Parkinson’s Disease’ section (page unavailable) reports elevated bulk protein synthesis linked to neurodegenerative phenotypes in a mutant LRRK2 fly model. It also links pink1 and parkin pathology to translation, but explicitly says there is no direct evidence that either gene dysregulates global mRNA translation in PD. Thus, the claim extends the bulk-synthesis finding beyond what the paper supports. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [9] source

  • May combine two claims.

    Premisecitation

    This aberrant protein synthesis is in part mediated by dysregulation of LRRK2 phosphorylation of ribosomal proteins and PINK1 and parkin modulation of 4E-BP.

    “This aberrant protein synthesis is, in part, mediated by dysregulation of LRRK2 phosphorylation of ribosomal proteins (5,6) and PTEN-induced kinase 1 (PINK1) and parkin modulation of eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP) (7).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [5] source
    • cites [6] source
    • cites [7] source

      The Results section ('4E-BP pathway is activated in parkin/PINK1 mutants'; page unavailable) reports altered 4E-BP phosphorylation in PINK1 and parkin mutants and links the pathway to global protein translation. It describes this change as a protective stress response, however, rather than showing that PINK1/parkin modulation of 4E-BP mediates aberrant protein synthesis. The LRRK2 ribosomal-protein clause has separate citations and is not assessed here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mitochondrial degeneration has been implicated in a-synucleinopathy and a-syn transgenic flies show abnormal mitochondrial morphology.

    “Mitochondrial degeneration has been implicated in a-synucleinopathy (13,25) and a-syn transgenic flies show abnormal mitochondrial morphology (16).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [13] source

      The citation to this paper is attached to the claim that mitochondrial degeneration has been implicated in α-synucleinopathy; the statement about transgenic flies has a separate citation. The Results describe α-synuclein, ubiquitin, and neurofilament abnormalities in transgenic mice, but searches for mitochondrial degeneration and mitochondrial morphology found no passage addressing the cited claim. Page numbers were not available in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [25] source
    • cites [16] source

  • May combine two claims.

    Premisecitation

    TSC1 is an HSP-90 co-chaperone and protects TSC2 from HERC1-mediated ubiquitination and degradation.

    “TSC1 is an HSP-90 co-chaperone and protects TSC2 from HERC1-mediated ubiquitination and degradation (29).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] source

      In “TSC1 Inhibits the Interaction between TSC2 and HERC1” (page unavailable), the paper proposes that TSC1 prevents TSC2 from interacting with HERC1, thereby inhibiting TSC2 ubiquitination and degradation. It presents this mechanism as possible and says further studies are needed to verify it. Our copy does not identify TSC1 as an HSP-90 co-chaperone. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims.

    Findingcitation

    Monomeric WT and A53T a-syn repress protein translation.

    “These findings taken together suggest that monomeric non-pathologic suppresses protein translation while pathologic a-syn enhances protein translation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Pathologic a-syn PFF causes dose-dependent disassembly of the TSC1-TSC2 complex, with 0.5 nM causing 50% dissociation.

    “The addition of pathologic a-syn PFF resulted in a dose dependent disassembly of the TSC1-TSC2 complex, and quantification revealed that 0.5 nM a-syn PFF resulted in the dissociation of 50% of the TSC1-TSC2 protein complex (Figure 6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ab oligomers and Tau PFF do not disassemble the TSC1-TSC2 complex.

    “Ab oligomers and Tau PFF do not disassemble the TSC1-TSC2 complex (Figure 6C) suggesting the destabilization of the TSC1-TSC2 protein complex is specific for pathologic a-syn.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rapamycin suppresses α-syn pathology and mTORC1 pathway in primary cortical neurons.

    “(K) Rapamycin suppresses a-syn pathology and mTORC1 pathway in primary cortical neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In primary a-syn PFF cortical neuronal model, 4E-BP1 overexpression significantly reduces enhanced protein translation and reduces P-S129 a-syn levels and neurotoxicity.

    “In the primary a-syn PFF cortical neuronal model, 4E-BP1 overexpression by Lentivirus significantly reduces the enhanced protein translation (Figure S6J) and significantly reduced P-S129 a-syn levels and neurotoxicity (Figures S6K andS6L).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Rapamycin significantly reduced loss of TH and Nissl positive neurons in α-syn PFF injected mice at six months.

    “Rapamycin significantly reduced the loss of both TH and Nissl positive neurons as determined using unbiased stereology (Figure 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no significant change TSC1-TSC2 protein levels and P-S129 a-syn was not detectable in the cerebellum.

    “There were no significant change TSC1-TSC2 protein levels and P-S129 a-syn was not detectable in the cerebellum, a relatively unaffected brain area in PD (Figure 7O).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    TSC1-TSC2 complex is stable in presence of increasing concentrations of α-syn monomer.

    “Figure: S5 Fig. S5 : Fig. S5: TSC1-TSC2 complex is stable in presence of increasing concentrations of a-syn monomer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both TH and DA neuron loss were rescued by 4E-BP1 overexpression.

    “Both TH and DA neuron loss were also rescued by 4E-BP1 overexpression (Figure S6C-S6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rapamycin significantly reduced a-syn PFF induced P-S129 a-syn levels and reduced a-syn PFF neurotoxicity.

    “Rapamycin also significantly reduced a-syn PFF induced P-S129 a-syn levels (Figure 3K and 3L) and it reduced a-syn PFF neurotoxicity (Figure 3M).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Dopamine neuron loss and locomotion defects in Syb-QF2> a-syn flies were reduced and lifespan was increased by rapamycin.

    “Dopamine neuron loss and locomotion defects in the Syb-QF2> a-syn flies were also reduced and lifespan was increased by feeding rapamycin (Figures 3E, 3F, 3H, 3I and Video S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    S6K is phosphorylated and activated in transgenic Drosophila models.

    “Consistent with mTOR activation, S6K is phosphorylated and activated in transgenic Drosophila models (Figures S4A andS4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inhibition of S6K prevented DA neuron loss and increased lifespan of Syb-QF2>α-syn flies.

    “Inhibition of S6K significantly prevented DA neuron loss and increased the lifespan of Syb-QF2>α-syn flies (Figure S4F andS4G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Anisomycin rescues α-syn pathology and neurotoxicity.

    “Figure: 5 Fig. 5 : Fig. 5: Anisomycin rescues a-syn pathology and neurotoxicity.(A) Immunoblots show significant a-”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Syb-QF2> a-syn flies, mitochondria are enlarged which was normalized in double transgenic flies.

    “In Syb-QF2> a-syn flies, mitochondria are enlarged which was essentially normalized in double transgenic flies comparable to Syb-QF2/+ control flies (Figures S6F-S6I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Anisomycin significantly reduced enhanced P-S129 a-syn phosphorylation and TH loss in syb-QF2>α-syn flies.

    “Feeding syb-QF2>α-syn flies, the global protein synthesis inhibitor, anisomycin, significantly reduced enhanced P-S129 a-syn phosphorylation (Figure 5B) and it reduced TH loss as determined by immunoblot analysis (Figure 5C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rapamycin feeding led to significant reduction in P-S129 a-syn and reduced S6K and 4E-BP1 phosphorylation at six months in α-syn PFF injected mice.

    “Rapamycin feeding also led to a significant reduction in P-S129 a-syn (Figures 4B and4C) and it reduced S6K and 4E-BP1 phosphorylation throughout the brain at six months in the α-syn PFF injected mice (Figures 4D and4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TSC2 overexpression significantly reduced P-S129 a-syn levels and TH loss.

    “TSC2 overexpression also significantly reduced P-S129 a-syn levels (Figure 7B) and TH loss as determined via immunoblot analysis (Figure 7C).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationown data

    Destabilization of TSC1-TSC2 complex by pathologic a-syn leads to activation of mTOR kinase.

    “First, is the activation of mTOR kinase.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    For each batch, five to ten technical replicates were performed to ensure an accurate reading at each time-point, and the average of the independent trials was used to calculate the percentage of flies with climbing defects.

    “For each batch five to ten technical replicates were performed to ensure an accurate reading at each time-point and average of the independent trials was used to calculate the percentage of flies with climbing defects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Relevant Syb-QF2/+ and Gal4/+ heterozygous flies were used as controls in the experiments.

    “For experimental control, the relevant Syb-QF2/+ and Gal4/+ (heterozygous) flies were used as controls in the experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Animal procedures followed guidelines and were approved by Johns Hopkins Medical Institute Animal Care and Use Committee.

    “All animal procedures following the guidelines of Laboratory Animal Manual of the National Institute of Health Guide to the Care and Use of Animals and upon approval of the Johns Hopkins Medical Institute Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Proteins identified as positive interactors were required to be identified via at least 2 separate peptides of at least 6 amino acids and enriched at least 2-fold.

    “In the mass spectrometric analysis, only proteins that were at identified via at least 2 separate peptides of at least 6 amino acids and enriched at least 2-fold were included as positive interactors in the human A53T a-syn-APEX (Figure 1C and Data Set S1) and the asyn PFF pull downs (Figure 1C and Data Set S2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The pole test measures bradykinesia.

    “The pole test was used to measure bradykinesia (Karl et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Karl et al., 2003

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Pathologic a-syn directly binds TSC2 and destabilizes TSC1-TSC2 complex and triggers aberrant mTORC1 activation, which results in enhanced mRNA translation and subsequent neurodegeneration.

    “Together, our data uncover a molecular mechanism by which pathologic a-syn directly binds to TSC2 and destabilizes the TSC1-TSC2 complex and triggers aberrant mTORC1 activation, which results in enhanced mRNA translation and subsequent neurodegeneration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A53T a-Syn-APEX2 transfected cells without H2O2 treatment were used as a control for immunoprecipitation.

    “To control the immunoprecipitation, A53T a-Syn-APEX2 transfected cells were used without H2O2 treatment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Unbiased stereology was used to determine neuron loss.

    “Rapamycin significantly reduced the loss of both TH and Nissl positive neurons as determined using unbiased stereology (Figure 4A).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A minimum of 500 molecules acquired from at least four different imaging areas were analyzed for each experimental condition.

    “A minimum of 500 molecules acquired from at least four different imaging areas were analyzed for each experimental condition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Rapamycin neutralizes increased protein translation and rescues PD pathology in Drosophila and mouse cortical neurons.

    “These findings suggest that pathologic a-syn mediated increase in translation depends on mTOR and that rapamycin neutralizes the increased protein translation and rescues PD pathology in Drosophila and mouse cortical neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Huntington's disease, pharmacological inhibition of mTOR by rapamycin is neuroprotective and attributed to activation of 4E-BP1 and inhibition of protein synthesis.

    “Similar to our findings in PD, in Huntington's disease, pharmacological inhibition of mTOR by rapamycin is neuroprotective and this effect is attributed to the activation of 4E-BP1 and inhibition of protein synthesis in Huntington's disease (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

  • May combine two claims.

    Interpretationown data

    These events are critically linked to neurodegeneration mediated by pathologic a-syn since restoration of TSC2, inhibition of mTOR, expression of 4E-BP1, inhibition of S6K or inhibition of protein translation exhibited neuroprotection.

    “These events are critically linked to neurodegeneration mediated by pathologic a-syn since restoration of TSC2 levels, inhibition of mTOR, expression of 4E-BP1, inhibition of S6K or inhibition of protein translation exhibited neuroprotection against pathologic a-syn.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The use of Lobind tubes significantly reduces the binding of hydrophobic proteins to the wall of the tubes.

    “as the use of these tubes significantly reduces the binding of hydrophobic proteins to the wall of the tubes (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] source

  • The quote only partly states this claim.

    Interpretationreasoning

    Destabilization leads to mTOR kinase phosphorylation of S6K.

    “Third, is mTOR kinase phosphorylation of S6K.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    How pathologic a-syn leads to degeneration in PD is poorly understood.

    “How pathologic a-syn leads to the degeneration in PD is poorly understood.”

  • The paper relies on this without support.

    A molecular mechanism accounting for dysregulation of protein homeostasis in PD is currently lacking.

    “A molecular mechanism accounting for this dysregulation is currently lacking.”

  • The paper relies on this without support.

    Whether aberrant protein translation plays a role in a-syn pathogenesis is not known.

    “Whether aberrant protein translation plays a role in role in a-syn pathogenesis is not known.”

  • The paper relies on this without support.

    Pathologic a-syn accumulation and formation is central to PD disease progression.

    “Central to the disease progression is the accumulation and the formation of pathologic a-synuclein (asyn).”

  • The paper relies on this without support.

    Microencapsulation protects rapamycin from digestion in the stomach.

    “Microencapsulation protects rapamycin from digestion in the stomach and the encapsulated rapamycin was administered at 14 mg per kg food (2.24 mg of rapamycin per kg body weight per day).”
5 of 5

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting schedules for the 30-day rapamycin injections

    Minor

    The results describe starting rapamycin on the day of PFF injection and administering it every two days. The methods instead say treatment began the following day and continued three times per week.

1 of 1

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Related

Authors
Khan, M. R., Yin, X., Kang, S.-U., Mitra, J., Wang, H., Brahmachari, S., Karuppagounder, S. S., Kimura, Y., Jhaldiyal, A., Kim, H. H., Gu, H., Chen, R., Redding-Ochoa, J., Troncoso, J., Ha, T., Dawson, V. L., & Dawson, T. M.
Affiliations
Johns Hopkins University (US)
Corresponding author
  • Dawson, Valina L.
  • Dawson, Ted M.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2022-10-06
DOI
10.1101/2022.10.03.510455
OpenAlex
W4302424503
Semantic Scholar
6d7c7200e47ea106dc96be108f79674107b406ba
Cited by
0
References
41
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
Funders
  • Howard Hughes Medical Institute
  • JPB Foundation
  • Johns Hopkins University
  • Diana Helis Henry Medical Research Foundation (H-2018)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Parkinson's disease, alpha-synuclein, mTORC1 signaling, mRNA translation, TSC1/TSC2 complex, tuberous sclerosis complex, proteostasis, neurodegeneration, dopaminergic neurons, alpha-synuclein preformed fibrils, Drosophila model, mTOR inhibition

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