TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models

It may state two separate claims as one.

TMEM55B is a TFEB/TFE3 target, with expression induced by starvation or lysosomal stress.

“TMEM55B is a TFEB/TFE3 target, with expression induced by starvation or lysosomal stress, suggesting transcriptional regulation of lysosomal positioning.”

• cites Sardiello et al. 2009 sourceNot checked — no full text of the source
• cites Martina et al. 2016 sourceCould not verify

  The section on lysosomal and autophagic genes reports TFEB/TFE3-dependent expression changes under ER stress for MCOLN1, ATP6V1C1, HEXA and UVRAG, and discusses their regulation under starvation. Searches for TMEM55B and lysosomal positioning found no passage establishing that TMEM55B is a TFEB/TFE3 target or that its expression is induced by starvation or lysosomal stress. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites Pastore et al. 2016 sourceCould not verify

  The Introduction and the section on TFE3 direct targets describe TFEB/TFE3 regulation of lysosomal genes under starvation, but do not identify TMEM55B as a target. Searches for TMEM55B and for lysosomal positioning or stress found no passage addressing its expression; the claim therefore cannot be verified from our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

TMEM55B regulates autophagosome-lysosome fusion, lysosomal repair, and TFE3 nuclear translocation under stress, interacts with amino-acid sensing complexes, and modulates cholesterol metabolism via PI(4,5)P2 phosphatase activity.

“TMEM55B also regulates autophagosome-lysosome fusion, lysosomal repair, and TFE3 nuclear translocation under stress (Jeong et al. 2024), interacts with amino-acid sensing complexes (Hashimoto et al. 2018), and modulates cholesterol metabolism via PI(4,5)P2 phosphatase activity (Qin et al. 2020).”

• cites Jeong et al. 2024 sourceSupported
• cites Hashimoto et al. 2018 sourceNot checked — no full text of the source
• cites Qin et al. 2020 sourcePartly supported

  The Results and Discussion report that TMEM55B regulates plasma cholesterol through changes in PI(4,5)P2 and LDLR lysosomal degradation. But the Discussion explicitly says the authors did not test TMEM55B’s phosphatase activity and that its effect on PI(4,5)P2 could be indirect, so the claimed mechanism is not established by this paper. The other functions in the sentence are attributed to different citations, not Qin et al. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Lysosomal positioning, modulated by cellular stimuli, regulates autophagic flux, and starvation-induced perinuclear lysosome-autophagosome fusion is critical for cargo degradation.

“Lysosomal positioning, modulated by cellular stimuli, regulates autophagic flux, and starvation-induced perinuclear lysosome-autophagosome fusion is critical for cargo degradation (Kimura et al. 2008), (Korolchuk et al. 2011).”

• cites Kimura et al. 2008 sourcePartly supported

  In “Anti-LC3 antibody microinjection inhibits autophagosome movement” (page unavailable), the paper reports faster delivery of autophagosome markers to perinuclear lysosomes during starvation and shows that inhibiting autophagosome movement impairs that delivery. It does not establish that stimulus-modulated lysosomal positioning regulates autophagic flux: it explicitly reports that starvation did not significantly change lysosome localization. The experiment measures delivery, not cargo degradation directly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Korolchuk et al. 2011 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Lysosomes act as amino-acid sensors through a complex involving vacuolar ATPase, Ragulator, and Rag GTPases that recruit mTORC1 to lysosomal membranes.

“Lysosomes act as amino-acid sensors through a complex involving vacuolar ATPase, Ragulator, and Rag GTPases that recruit mTORC1 to lysosomal membranes (Laplante and Sabatini 2012).”

• cites Laplante and Sabatini 2012 sourceSupported

It may state two separate claims as one.

TMEM55B over-expression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery.

“TMEM55B over-expression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery.”

• cites Willett et al. 2017 sourceSupported

Probably not a substantial claim.

LAMP2 (along with LAMP1) is a structural lysosomal membrane protein marker used to identify lysosomes and late endo/lysosomal compartments.

“LAMP2 (along with LAMP1) is widely accepted as a structural lysosomal membrane protein marker used to identify lysosomes and late endo/lysosomal compartments”

• cites Klionsky et al. 2021 sourceSupported
• cites Eskelinen et al. 2002 sourceNot checked — no full text of the source
• cites Saftig and Klumperman 2009 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Neurodegeneration is linked to impaired autophagy and trafficking.

“Neurodegeneration is linked to impaired autophagy and trafficking (Dobrowolski and De Robertis 2011), (Sorkin and von Zastrow 2009), (Taelman et al. 2010), (Killisch et al. 1991), (Lipinski et al. 2010), (Nixon 2013).”

• cites Dobrowolski and De Robertis 2011 sourceCould not verify

  The section “A broader role for sequestration?” discusses endosomal trafficking in growth-factor signalling, and the copy describes microautophagy in multivesicular endosomes. Neither passage links impaired autophagy or trafficking to neurodegeneration. Searches for “neurodegeneration” and related disease terms found no such link in our copy; page numbers were not provided. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites Sorkin and von Zastrow 2009 sourceCould not verify

  The section “Retrograde endosome signalling in neurons” describes endosomal transport as necessary for neuronal survival signalling, but does not link impaired trafficking to neurodegeneration. Searches for “autophagy,” “neurodegeneration,” and Alzheimer’s disease found no passage in our copy establishing the claimed link. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites Taelman et al. 2010 sourceCould not verify

  The Discussion section, “A Positive Role for Endocytosis in Signal Transduction” (page unavailable), describes endosomal trafficking in Wnt signaling and mentions possible implications for human disease, including cancer. Our copy does not link impaired trafficking or autophagy to neurodegeneration; searches for “autophagy” and “neurodegeneration” found no passage making that link. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

TMEM55B associates with V-ATPase/Ragulator to regulate mTORC1 and controls PI(4,5)P2-dependent LDLR and cholesterol metabolism.

“TMEM55B associates with V-ATPase/Ragulator to regulate mTORC1 (Hashimoto et al. 2018) and controls PI(4,5)P2-dependent LDLR and cholesterol metabolism (Qin et al. 2020).”

• cites Hashimoto et al. 2018 sourceNot checked — no full text of the source
• cites Qin et al. 2020 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Chloroquine primarily blocks autophagosome-lysosome fusion rather than simply alkalinizing lysosomes.

“CQ primarily blocks autophagosome-lysosome fusion rather than simply alkalinizing lysosomes.”

• cites Mauthe et al. 2018 sourceSupported

Borderline substantial claim. It is unclear why the paper says it holds.

TMEM55B is lowered in iPSC derived neurons derived from AD patients.

“TMEM55B is lowered in iPSC derived neurons derived from AD patients.”

It may state two separate claims as one.

Day 20 neurons exhibited mature neuronal morphology but did not display overt AD-associated phenotypes.

“Consistent with this rationale, day 20 neurons exhibited mature neuronal morphology but did not display overt AD-associated phenotypes (Figure 9B, Biv).”

It may state two separate claims as one. The quote only partly states this claim.

Loss of dTMEM55 function in Drosophila (heterozygous mutant, motor neuron RNAi, pan-neuronal RNAi, knockout) causes locomotory/climbing defects at 10 days but not at 3 days of age.

“In a similar fashion, the dTMEM55 knockout flies (CG6707 KO / +) also displayed climbing defects in older flies (10 days old) and not in the 3 days old younger flies [Supplementary Figure 7B, 7C].”

It may state two separate claims as one.

An increase in p-Tau levels in the lysosomes located in the soma of the 40 day old AD iPSC derived forebrain neurons in comparison to p-Tau levels in the soma of 40 days old Control neurons and not in 20 days old AD iPSC neurons.

“We observed that an increase in p-Tau levels in the lysosomes located in the soma of the 40 day old AD iPSC derived forebrain neurons [Figure 7Fiii, 7B] in comparison to p-Tau levels in the soma of 40 days old Control neurons [Figure 7Eiii, 7B], [Figure 9Biii, 9Bv] and not in 20 days old AD iPSC neurons”

It may state two separate claims as one.

There was no autophagic flux defects in the AD iPSCs and the levels of autophagic flux in the AD iPSCs were comparable to the Control iPSCs.

“There was no autophagic flux defects in the AD iPSCs and the levels of autophagic flux in the AD iPSCs were comparable to the Control iPSCs [Fig 9 Ai].”

It may state two separate claims as one.

We were able to rescue the climbing defects in 10day old flies, indicating the vital and specific role of dTMEM55 in maintaining optimum neuronal function and output.

“We were able to rescue the climbing defects in 10day old flies, indicating the vital and specific role of dTMEM55 in maintaining optimum neuronal function and output.”

It may state two separate claims as one.

TMEM55B levels were lowered in dTMEM55 loss of function flies and elevated in the dTMEM55 gain of function flies.

“We found that the TMEM55B levels were lowered in dTMEM55 loss of function flies and elevated in the dTMEM55 gain of function flies.”

It may state two separate claims as one.

Expression of housekeeping genes (RPL13A, GAPDH) remained stable across control and AD groups, confirming that the observed changes were not due to global transcriptional decline.

“Expression of housekeeping genes (RPL13A, GAPDH) remained stable across control and AD groups, confirming that the observed changes were not due to global transcriptional decline.”

It may state two separate claims as one.

Tuj-1, Tau, and Synapsin were elevated in mature differentiated neurons (both 20-day and 40-day) and were missing from iPSCs.

“All the three neuronal markers were elevated in the mature differentiated neurons [both 20-days and 40-days] and were missing from the iPSCs.”

It may state two separate claims as one.

Misexpression of both human Tau with a concomitant downregulation of dTMEM55 resulted in a more severe rough eye, with the abnormal phenotype extending farther posteriorly.

“Misexpression of both human Tau with a concomitant downregulation of dTMEM55 resulted in a more severe rough eye, with the abnormal phenotype extending farther posteriorly.”

It may state two separate claims as one.

There were no autophagic flux defects in AD iPSCs; levels of autophagic flux in AD iPSCs were comparable to control iPSCs.

“There was no autophagic flux defects in the AD iPSCs and the levels of autophagic flux in the AD iPSCs were comparable to the Control iPSCs.”

It may state two separate claims as one.

In the same cohort, severe AD samples exhibited downregulation of the lysosomal gene MCOLN1 and concomitant upregulation of the AD-associated gene MAPT, consistent with progressive Tau pathology.

“In the same cohort, severe AD samples exhibited downregulation of the lysosomal gene MCOLN1 and concomitant upregulation of the AD-associated gene MAPT, consistent with progressive Tau pathology.”

It may state two separate claims as one.

iPSCs showed high levels of OCT4, while 20-day and 40-day old neurons lacked OCT4 signal.

“The iPSCs showed high levels of OCT4, while the 20-days and 40-days old neurons lacked OCT4 signal.”

It may state two separate claims as one.

Loss of function of dTMEM55 leads to locomotion defects, enhances lethality, accumulation of lysosomes in axonal nerves, and enhances Tau-mediated neurodegeneration.

“We observed that the loss of function of dTMEM55 [Drosophila TMEM] leads to locomotion defects, enhances lethality, accumulation of lysosomes in the axonal nerves, enhances Tau-mediated neurodegeneration.”

It may state two separate claims as one.

Both dTMEM55 mutant flies and flies with RNAi mediated TMEM55B downregulation using a motor neuron and pan-neuronal driver showed locomotory defects in 10 days old flies.

“Both dTMEM55 mutant flies and flies with RNAi mediated TMEM55B downregulation using a motor neuron and pan-neuronal driver showed locomotory defects in 10 days old flies.”

It may state two separate claims as one.

The dTMEM mutant and duplication lines have lower and higher dTMEM mRNA levels than wild type, respectively.

“dTMEM mRNA transcripts are lower and higher than the wild type in the CG6707c / + (dTMEM mutant) and CGDup / + (dTMEM Duplication) lines.”

It may state two separate claims as one.

Downregulation of dTMEM enhances Tau-mediated locomotory dysfunction and lethality.

“Downregulation of dTMEM enhances Tau-mediated locomotory dysfunction and lethality.”

It may state two separate claims as one.

Loss of dTMEM and trpml leads to increased lethality and decline in survival.

“Loss of dTMEM and trpml leads to enhanced locomotory defects, lethality and decline in survival of the animals.”

It may state two separate claims as one. The quote only partly states this claim.

Loss of dTMEM and trpml leads to increased accumulation of nuclear cleaved caspase 3 and increased cell death.

“Loss of dTMEM and trpml leads to increased accumulation of nuclear cleaved caspase 3 and increase in the number of”

It may state two separate claims as one.

Overexpression of dTMEM or human TMEM55 in glutamatergic neurons rescues locomotory defects in CG6707c mutant flies.

“Overexpression of dTMEM in glutamatergic neurons rescues locomotory defects in CG6707c mutant flies”

• Also stated in: § TUNEL positive cells. · plain

  “Overexpression of humanTMEM55 (driven by OK371 Gal4 driver and various UAS human TMEM55 lines) in glutamatergic neurons rescues locomotory defects in CG6707c mutant flies”

It may state two separate claims as one.

Rab7 staining spanned a greater length in the soma and covered more distance from the nucleus in si-TMEM55B HEK293T cells compared to control.

“Rab7 staining spanned a greater length in the soma and covered more distance from the nucleus, covering both the perinuclear and peripheral regions of the HEK293T cells treated with si-TMEM55B RNA.”

It may state two separate claims as one.

Downregulation of dTMEM using the UAS RNAi line decreases dTMEM levels, and overexpression using the UAS dTMEM mcherry line increases endogenous dTMEM levels.

“Downregulation of dTMEM using the UAS RNAi line leads to decrease levels than the Gal4 driver or UAS responder alone.”

• Also stated in: § Additional information · plain

  “Overexpression of dTMEM using the UAS dTMEM mcherry line leads to an increase in the levels of endogenous dTMEM.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The transcription factors TFEB and TFE3 act as master regulators of lysosomal biogenesis.

“The transcription factors TFEB and TFE3 act as master regulators of lysosomal biogenesis (Sardiello et al. 2009), (Martina et al. 2014).”

• cites Sardiello et al. 2009 sourceNot checked — no full text of the source
• cites Martina et al. 2014 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Activation of mTORC1 by Rheb downstream of growth-factor signaling controls lysosomal and autophagosome biogenesis via TFEB and the CLEAR gene network.

“Activation of mTORC1 by Rheb downstream of growth-factor signaling (Inoki et al. 2003), (Tee et al. 2003), controls lysosomal and autophagosome biogenesis via TFEB and the CLEAR gene network (Sardiello et al. 2009), (Settembre et al. 2012).”

• cites Inoki et al. 2003 sourceNot checked yet
• cites Tee et al. 2003 sourceNot checked yet

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

• cites Sardiello et al. 2009 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Dysfunctional autophagosomes and lysosomes are early pathological features in Alzheimer's disease (AD), preceding the classical deposition of amyloid-β plaques and Tau-containing neurofibrillary tangles.

“Dysfunctional autophagosomes and lysosomes are recognized as early pathological features in Alzheimer's disease (AD), preceding the classical deposition of amyloid-β plaques and Tau-containing neurofibrillary tangles (Nixon and Yang 2011).”

• cites Nixon and Yang 2011 sourceNot checked yet

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

It may state two separate claims as one.

TMEM55B levels are lowered in the neuronal population of AD patients, hinting at a possible link between TMEM55B downregulation and neuronal degeneration.

“This indicates that TMEM55B levels are lowered in the neuronal population of AD patients, and hints towards a possible link of this TMEM55B downregulation in neuronal degeneration.”

It may state two separate claims as one.

Inefficient clearance of Tau due to autophagic flux defects leads to its accumulation, leading to neuronal degeneration.

“Inefficient clearance of Tau due to autophagic flux defects leads to its accumulation, leading to neuronal degeneration.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

TMEM55B is a lysosomal protein implicated in regulating lysosomal positioning and phosphatidylinositol 5-monophosphate abundance in the nucleus.

“TMEM55B is a lysosomal protein implicated in regulating lysosomal positioning and phosphatidylinositol 5-monophosphate abundance in the nucleus (Ungewickell et al. 2005), (Zou et al. 2007).”

• cites Ungewickell et al. 2005 sourceNot checked — no full text of the source
• cites Zou et al. 2007 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Activation of TFEB and TFE3 results in a significant increase in TMEM55B mRNA and protein levels.

“Activation of TFEB and TFE3 resulted in a significant increase in TMEM55B mRNA and protein levels, supporting a role for these transcription factors in modulating TMEM55B expression (Willett et al. 2017) .”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Polymorphisms in several lysosomal cathepsin genes are associated with increased AD susceptibility.

“Genetic studies further support lysosomal involvement, as polymorphisms in several lysosomal cathepsin genes are associated with increased AD susceptibility (Bhojak et al. 2001), (Papassotiropoulos et al. 1999).”

• cites Bhojak et al. 2001 sourceNot checked — no full text of the source
• cites Papassotiropoulos et al. 1999 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Neuronal culture purity was assessed by immunocytochemistry and Western blot analysis using established neuronal and brain-specific markers.

“Neuronal culture purity was assessed by immunocytochemistry and Western blot analysis using established neuronal and brain-specific markers.”

It may state two separate claims as one.

TMEM55B recruits the dynein adaptor JIP4 to lysosomes, promoting retrograde transport, while depletion of TMEM55B or JIP4 causes peripheral lysosome accumulation.

“It recruits the dynein adaptor JIP4 to lysosomes, promoting retrograde transport, while depletion of TMEM55B or JIP4 causes peripheral lysosome accumulation (Willett et al. 2017).”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim.

Impairment of the autophagosome-lysosomal system and the resulting disruption of intracellular signaling and trafficking are strongly linked to neurodegeneration.

“Together, impairment of the autophagosome-lysosomal system and the resulting disruption of intracellular signaling and trafficking have been strongly linked to neurodegeneration (Sorkin and von Zastrow 2009;Dobrowolski and De Robertis 2011), (Taelman et al. 2010), (Killisch et al. 1991), (Lipinski et al. 2010), (Nixon 2013).”

• cites Sorkin and von Zastrow 2009 sourceNot checked yet

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

• cites Dobrowolski and De Robertis 2011 sourceNot checked yet

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

• cites Nixon 2013 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Deletion of the lysosomal protease inhibitors cystatin B/C ameliorates AD-related phenotypes in mice.

“In addition, deletion of the lysosomal protease inhibitors cystatin B/C has been reported to ameliorate AD-related phenotypes in mice (Mi et al. 2007), (Yang et al. 2011), (Yang et al. 2014).”

• cites Mi et al. 2007Not matched

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

• cites Yang et al. 2011 sourceNot checked yet
• cites Yang et al. 2014 sourceNot checked yet

It may state two separate claims as one.

TMEM55B levels are dysregulated in severe AD patients and not in mild or moderate AD cases.

“These results indicate that TMEM55B levels are dysregulated in severe AD patients and not in mild or moderate AD cases.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Post-translational modifications, including S-palmitoylation and Erk/MAPK-mediated phosphorylation, modulate TMEM55B function.

“Post-translational modifications, including S-palmitoylation and Erk/MAPK-mediated phosphorylation, further modulate TMEM55B function (Takemasu et al. 2019).”

• cites Takemasu et al. 2019 sourceNot checked — no full text of the source

Probably not a substantial claim. It may state two separate claims as one.

Swelling of endosomal compartments enriched in amyloid precursor protein (APP) peptides, lysosomal deficits, and abnormal accumulation of autophagic vacuoles have been observed in human AD brains and corresponding mouse models.

“Swelling of endosomal compartments enriched in amyloid precursor protein (APP) peptides (Takahashi et al. 2002), lysosomal deficits, and abnormal accumulation of autophagic vacuoles have been observed in human AD brains and corresponding mouse models (Cataldo et al. 1997), (Nixon and Yang 2011), (Nixon et al. 2005).”

• cites Cataldo et al. 1997 sourceNot checked yet

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

• cites Nixon and Yang 2011 sourceNot checked yet

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

• cites Nixon et al. 2005 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

All analyses were performed with the experimenter blinded to genotype.

“All analyses were performed with the experimenter blinded to genotype (Roy and Jackson 2014).”

• cites Roy and Jackson 2014 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Autophagy is essential for the removal of protein aggregates, damaged proteins, and dysfunctional organelles, whose accumulation is implicated in AD and other neurodegenerative disorders.

“Autophagy is essential for the removal of protein aggregates, damaged proteins, and dysfunctional organelles, whose accumulation is implicated in AD and other neurodegenerative disorders (Nixon 2013).”

• cites Nixon 2013 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

MCOLN1 mediates lysosomal Ca2+ release to activate calcineurin, promoting TFEB nuclear translocation, autophagy, and lysosomal biogenesis.

“MCOLN1, which mediates lysosomal Ca²⁺ release to activate calcineurin, promoting TFEB nuclear translocation, autophagy, and lysosomal biogenesis (Medina and Ballabio 2015), (Medina et al. 2015).”

• cites Medina and Ballabio 2015Not matched

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

• cites Medina et al. 2015Not matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Cells were routinely tested for mycoplasma contamination.

“were routinely tested for mycoplasma contamination using the MycoAlert™ PLUS Mycoplasma Detection Kit (PlasmoTest™ -Mycoplasma Detection Kit, invivogen Cat.code: rep-pt1) according to the manufacturer's instructions.”

It may state two separate claims as one.

These findings position TMEM55B as a modulator of Tau-dependent neurotoxicity and implicate it in pathways governing Tau phosphorylation and clearance.

“These findings position TMEM55B as a modulator of Tau-dependent neurotoxicity and implicate it in pathways governing Tau phosphorylation and clearance.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

In NFTs, Tau is hyperphosphorylated and tau kinases such as GSK-3β, MARK and Cdk5 are widely believed to play a role in the formation of insoluble tau aggregates and NFTs.

“In the NFT, Tau is hyperphosphorylated and it is widely believed that tau kinases such as glycogen synthase kinase-3β (GSK)-3β, microtubule affinity-regulating kinase (MARK) and cyclin-dependent kinase 5 (Cdk5) play a role in the formation of insoluble tau aggregates and NFT (Cho and Johnson 2003), (Augustinack et al. 2002).”

• cites Cho and Johnson 2003 sourceNot checked — no full text of the source
• cites Augustinack et al. 2002 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Presenilin-1 (PSEN1) is the catalytic core of the γ-secretase complex and mediates intramembrane cleavage of APP, generating Aβ peptides that accumulate as extracellular plaques, a defining neuropathological hallmark observed in all postmortem AD brains.

“Presenilin-1 (PSEN1), the catalytic core of the γ-secretase complex, mediates intramembrane cleavage of the amyloid precursor protein (APP), generating amyloid-β (Aβ) peptides that accumulate as extracellular plaques, a defining neuropathological hallmark observed in all postmortem Alzheimer's disease (AD) brains (Haass and Selkoe 1993), (De Strooper et al. 2012).”

• cites Haass and Selkoe 1993 sourceNot checked — no full text of the source
• cites De Strooper et al. 2012Not matched

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

It may state two separate claims as one.

Both control and PSEN1 M146L iPSCs expressed high levels of OCT3/4, which was absent in day 20 and day 40 neurons, confirming loss of pluripotency upon differentiation.

“Both control and PSEN1 M146L iPSCs expressed high levels of OCT3/4, which was absent in day 20 and day 40 neurons, confirming loss of pluripotency upon differentiation (Supplementary Figure 10 B).”

It may state two separate claims as one.

Morphological assessment and immunocytochemical analyses confirmed the generation of a high proportion of mature neurons, underscoring the robustness and consistency of the NGN2-driven differentiation protocol.

“Morphological assessment and immunocytochemical analyses further confirmed the generation of a high proportion of mature neurons, underscoring the robustness and consistency of the NGN2-driven differentiation protocol.”

It may state two separate claims as one.

These observations validate the temporal disease relevance of the model and establish a framework for interrogating TMEM55B-dependent mechanisms underlying Tau pathology in human neurons.

“These observations validate the temporal disease relevance of the model and establish a framework for interrogating TMEM55B-dependent mechanisms underlying Tau pathology in human neurons.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

NGN2-mediated transcription factor programming enables rapid and efficient generation of functionally mature neurons while preserving robust expression of mature neuronal markers.

“Neuronal differentiation was achieved using NGN2-mediated transcription factor programming (Zhang et al. 2013b), a strategy that enables rapid and efficient generation of functionally mature neurons while preserving robust expression of mature neuronal markers (Ho et al. 2016;Hulme et al. 2022).”

• cites Zhang et al. 2013bNot matched

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

• cites Ho et al. 2016Not matched

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

• cites Hulme et al. 2022Not matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The differentiation protocol was optimized by integrating established principles of neuronal development to ensure reproducibility and high neuronal purity.

“The differentiation protocol was further optimized by integrating established principles of neuronal development to ensure reproducibility and high neuronal purity (Lancaster et al. 2013;Lancaster and Knoblich 2014a;Lancaster and Knoblich 2014b).”

• cites Lancaster et al. 2013 sourceNot checked yet
• cites Lancaster and Knoblich 2014aNot matched

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

• cites Lancaster and Knoblich 2014bNot matched

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

It may state two separate claims as one.

Studies using human iPSC-derived neurons demonstrate that the PSEN1 M146L mutation significantly elevates the Aβ42/Aβ40 ratio by selectively increasing Aβ42 production without altering Aβ40 levels, a biochemical signature strongly linked to amyloid aggregation and neurotoxicity in AD.

“Moreover, studies utilizing human induced pluripotent stem cell (iPSC)-derived neurons demonstrate that the M146L mutation significantly elevates the Aβ42/Aβ40 ratio by selectively increasing Aβ42 production without altering Aβ40 levels, a biochemical signature strongly linked to amyloid aggregation and neurotoxicity in AD (Liu et al. 2014), (Sproul et al. 2014), (Schrank et al. 2020).”

• cites Liu et al. 2014 sourceNot checked yet

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

• cites Sproul et al. 2014 sourceNot checked yet

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

• cites Schrank et al. 2020 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Among known FAD mutations, variants in presenilin-1 (PSEN1) are the most prevalent, with the M146L mutation being one of the best-characterized disease-causing alleles.

“Among known FAD mutations, variants in presenilin-1 (PSEN1) are the most prevalent, with the M146L mutation being one of the best-characterized diseasecausing alleles (Mangone et al. 1995;Morelli et al. 1998).”

• cites Mangone et al. 1995 sourceNot checked — no full text of the source
• cites Morelli et al. 1998 sourceNot checked — no full text of the source

It may state two separate claims as one.

Bulk RNA-seq and microarray analyses from the ROS-MAP dataset on total lysates of the dorsolateral prefrontal cortex cannot distinguish cell type-specific changes in TMEM55B expression and may be confounded by non-neuronal cell types including glia.

“Because bulk RNA-seq and microarray analyses from the ROS-MAP dataset were performed on total lysates of the dorsolateral prefrontal cortex, cell type-specific changes in TMEM55B expression cannot be distinguished and may be confounded by contributions from non-neuronal cell types, including glia.”

It may state two separate claims as one.

TMEM55B downregulation occurs at both transcript and protein levels and manifests during later stages of neuronal maturation.

“demonstrating that TMEM55B downregulation occurs at both transcript and protein levels and manifests during later stages of neuronal maturation”

It may state two separate claims as one.

Loss of function dTMEM55 elevates phosphorylated Tau levels, a clinical-pathological manifestation known to be associated with neurofibrillary tangles in AD.

“This indicates that loss of function dTMEM55 elevates phosphorylated Tau levels, a clinical-pathological manifestation known to be associated with neurofibrillary tangles in AD.”

• Also stated in: § Discussion: · hedged

  “This indicates that loss of function dTMEM55 elevates phosphorylated Tau levels, a clinical-pathological manifestation known to be associated with neurofibrillary tangles in AD.”

It may state two separate claims as one.

Downregulation of dTMEM55 enhanced Tau-mediated neuronal degeneration, dysfunction and toxicity in fly transgenic AD models, indicating that these neuronal defects might lead to neurodegeneration in AD patients.

“All these assays, including retinal degeneration, climbing defects and lethality showed that the downregulation of dTMEM55 enhanced Tau mediated neuronal degeneration, dysfunction and toxicity in the fly transgenic AD models, indicating that these neuronal defects might lead to neurodegeneration in AD patients.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Familial Alzheimer's disease (FAD) accounts for fewer than 5% of AD cases; sporadic and familial forms share substantial phenotypic and molecular overlap, likely reflecting convergence on common pathogenic pathways.

“Familial Alzheimer's disease (FAD) accounts for fewer than 5% of AD cases; however, sporadic and familial forms share substantial phenotypic and molecular overlap, likely reflecting convergence on common pathogenic pathways (Duara et al. 1993;Lippa et al. 1996).”

• cites Duara et al. 1993 sourceNot checked — no full text of the source
• cites Lippa et al. 1996 sourceNot checked — no full text of the source

It may state two separate claims as one.

An accumulation of p-Tau in the lysosomes upon downregulation of TMEM55B suggests defects in lysosomal mediated autophagic clearance of p-Tau, leading to neuronal degeneration by abnormal buildup of pathological forms of Tau.

“an accumulation of p-Tau in the lysosomes upon downregulation of TMEM55B suggests defects in lysosomal mediated autophagic clearance of p-Tau, leading to neuronal degeneration by abnormal buildup of pathological forms of Tau.”

• AssumptionRests on an assumption: The formation of phosphorylated form of Tau and its accumulation is associated with the formation of neuropathological hallmarks (NFTs) in the AD brains.

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In Drosophila models of neurodegeneration, including tauopathy and amyloid-β overexpression models, TUNEL has been reliably used to quantify neuronal apoptosis.

“In Drosophila models of neurodegeneration, including tauopathy and amyloid-β overexpression models, TUNEL has been reliably used to quantify neuronal apoptosis.”

• cites Wittmann et al. 2001 sourceNot checked — no full text of the source

It may state two separate claims as one.

These results suggest a possible defect in lysosome mediated autophagic clearance of p-Tau in the aged and severe AD patients, leading to neurodegeneration.

“These results in the iPSC derived neurons, suggests a possible defect in lysosome mediated autophagic clearance of p-Tau in the aged and severe AD patients, leading to neurodegeneration.”

• AssumptionRests on an assumption: The formation of phosphorylated form of Tau and its accumulation is associated with the formation of neuropathological hallmarks (NFTs) in the AD brains.

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Tau is a component of neurofibrillary tangles (NFT) in Alzheimer's disease and related tauopathies.

“The microtubule-binding protein tau is a component of neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and related disorders that are collectively referred to as tauopathies (Morishima-Kawashima et al. 1995), (Johnson and Bailey 2002).”

• cites Morishima-Kawashima et al. 1995 sourceNot checked — no full text of the source
• cites Johnson and Bailey 2002 sourceNot checked — no full text of the source

It may state two separate claims as one.

Downregulation of TMEM55b could potentially lead to elevated p-Tau, whose excessive accumulation could lead to formation of NFTs, leading to neuronal degeneration in AD.

“Thus, downregulation of TMEM55b could be potentially leading to elevated p-Tau, whose excessive accumulation could lead to formation of NFTs, leading to neuronal degeneration in AD.”

• Also stated in: § Discussion: · hedged

  “Thus, downregulation of TMEM55b could be potentially leading to elevated p-Tau, whose excessive accumulation could lead to formation of NFTs, leading to neuronal degeneration in AD.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

These organelles were observed to be multi-lamellar and multivesicular in nature by electron microscopy studies.

“These organelles were observed to be multi-lamellar and multivesicular in nature by electron microscopy studies (Terry et al. 1964)”

• cites Terry et al. 1964Not matched

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

It may state two separate claims as one.

Mature neuronal markers including class III β-tubulin (TUJ1), tau, and synapsin were robustly expressed in neurons at both day 20 and day 40 and were undetectable in iPSCs, demonstrating successful neuronal lineage commitment.

“Conversely, mature neuronal markers including class III β-tubulin (TUJ1), tau, and synapsin were robustly expressed in neurons at both time points and were undetectable in iPSCs, demonstrating successful neuronal lineage commitment.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

The PSEN1 M146L mutation enhances γ-secretase activity toward noncanonical substrates, including increased cleavage of STIM1, implicating dysregulated calcium homeostasis in disease progression.

“Functionally, the PSEN1 M146L mutation has been shown to enhance γ-secretase activity toward noncanonical substrates, including increased cleavage of the endoplasmic reticulum calcium sensor STIM1, thereby implicating dysregulated calcium homeostasis in disease progression (Tong et al. 2016).”

• cites Tong et al. 2016 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Free Ca2+ stored within lysosomes is a significant source of intracellular Ca2+ comparable to stores in the ER.

“Free Ca2+ stored within lysosomes, is a significant source of intracellular Ca2+ comparable to stores in the ER (Patel and Docampo 2010)”

• cites Patel and Docampo 2010 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

AD brains show enlarged APP-positive endosomes, lysosomal deficits, and autophagic vacuole accumulation.

“AD brains show enlarged APP-positive endosomes (Takahashi et al. 2002), lysosomal deficits, and autophagic vacuole accumulation (Cataldo et al. 1997), (Nixon and Yang 2011), (Nixon et al. 2005).”

• cites Takahashi et al. 2002 sourceNot checked yet
• cites Cataldo et al. 1997 sourceNot checked yet

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

• cites Nixon and Yang 2011 sourceNot checked yet

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

It may state two separate claims as one.

The lysosomal protein TMEM55B interacts and recruits the dynein adaptor JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules.

“They found that the lysosomal protein TMEM55B interacts and recruits the dynein adaptor JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules.”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect.

“Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect.”

• cites Medina and Ballabio 2015Not matched

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

• cites Medina et al. 2015Not matched

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

It may state two separate claims as one.

TMEM55B mediates PLEKHM1 degradation, ESCRT repair, and TFE3 activation.

“TMEM55B mediates PLEKHM1 degradation, ESCRT repair, and TFE3 activation (Jeong et al. 2024).”

• cites Jeong et al. 2024 sourceNot checked yet

Probably not a substantial claim.

Independent studies have suggested TMEM55B as a potential transcriptional target of TFEB and TFE3.

“Independent studies have further suggested TMEM55B as a potential transcriptional target of TFEB and TFE3 (Sardiello et al. 2009{Pastore, 2016 #194;Martina et al. 2016;Pastore et al. 2016).”

• cites Sardiello et al. 2009 sourceNot checked — no full text of the source
• cites Martina et al. 2016 sourceNot checked yet
• cites Pastore et al. 2016 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction.

“Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction.”

• cites Medina and Ballabio 2015Not matched

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

• cites Medina et al. 2015Not matched

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

It may state two separate claims as one.

These findings support the results observed by Puertollano and co-workers, and thus hint towards a possible mechanism of TMEM55B downregulation in AD patients, leading to lysosome positioning defects.

“These findings support the results observed by Puertollano and co-workers, and thus hint towards a possible mechanism of TMEM55B downregulation in AD patients, leading to lysosome positioning defects.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Puertollano and coworkers showed TMEM55B recruits JIP4 to lysosomes, promoting dynein-dependent retrograde transport, and depletion causes peripheral lysosome accumulation without affecting endosomes or Golgi.

“Puertollano and coworkers (Willett et al. 2017) showed TMEM55B recruits JIP4 to lysosomes, promoting dynein-dependent retrograde transport, and depletion causes peripheral lysosome accumulation without affecting endosomes or Golgi.”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Cathepsin polymorphisms increase AD risk, whereas cystatin B/C deletion improves phenotypes.

“Cathepsin polymorphisms increase AD risk (Bhojak et al. 2001), (Papassotiropoulos et al. 1999), whereas cystatin B/C deletion improves phenotypes (Mi et al. 2007), (Yang et al. 2011), (Yang et al. 2014).”

• cites Bhojak et al. 2001 sourceNot checked — no full text of the source
• cites Papassotiropoulos et al. 1999 sourceNot checked — no full text of the source
• cites Mi et al. 2007Not matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Lysosomal Ca2+ efflux via TRPML1 is activated in several stress conditions, including starvation, lysosome deacidification and oxidative stress, as well as during physiological processes such as phagocytosis of large particles by macrophages.

“Lysosomal Ca2+ efflux via TRPML1 is activated in several stress conditions, including starvation (Li et al. 2016), (Medina et al. 2015) , lysosome deacidification (Lee et al. 2015), (Raychowdhury et al. 2004) and oxidative stress (Zhang et al. 2016) , as well as during physiological processes such as phagocytosis of large particles by macrophages (Samie et al. 2013).”

• cites Li et al. 2016Not matched

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

• cites Medina et al. 2015Not matched

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

• cites Lee et al. 2015 sourceNot checked yet

It may state two separate claims as one.

Disruption of endosomal trafficking phenocopies CQ-induced fusion blockade and exacerbates neurodegeneration.

“disruption of endosomal trafficking phenocopies CQ-induced fusion blockade and exacerbates neurodegeneration (Kodani et al. 2019).”

• cites Nnah et al. 2019Not matched

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

• cites Kodani et al. 2019 sourceNot checked yet

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

Probably not a substantial claim. It may state two separate claims as one.

TMEM55B is a target of TFEB and TFE3, and TFEB and TFE3 modulate lysosomal positioning in response to nutrient deprivation and lysosomal stress by regulating TMEM55B expression levels.

“Since TMEM55B is a target of TFEB and TFE3, they proposed that, by regulating TMEM55B, expression levels [either by TFEB/3 activation by starvation or cholesterol accumulation in lysosomes]; TFEB and TFE3 modulate lysosomal positioning in response to nutrient deprivation and lysosomal stress.”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

These lysosome position defects could explain the continued presence of lysosomes and late endosomes in the peripheral and not the perinuclear region, preventing their fusion to the autophagosomes and impaired clearance of p-Tau leading to its excessive cellular accumulation.

“These lysosome position defects could explain the continued presence of lysosomes and late endosomes in the peripheral and not the perinuclear region, preventing their fusion to the autophagosomes and impaired clearance of p-Tau leading to its excessive cellular accumulation.”

• AssumptionRests on an assumption: These organelles were found to be relatively deficient in multiple lysosomal proteases and may arise due to a failure of optimal retrograde axonal lysosome transport near the amyloid plaques.

It may state two separate claims as one.

Reduction of either TMEM55B or JIP4 caused a dramatic accumulation of lysosomes at the cell periphery without affecting the distribution of early endosomes or the Golgi apparatus.

“They also found that reduction of either TMEM55B or JIP4 caused a dramatic accumulation of lysosomes at the cell periphery without affecting the distribution of early endosomes or the Golgi apparatus.”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

S-palmitoylation regulates TMEM55B trafficking, while ERK/MAPK-mediated phosphorylation controls perinuclear clustering.

“S-palmitoylation regulates its trafficking (Rudnik et al. 2022), while ERK/MAPK-mediated phosphorylation controls perinuclear clustering (Takemasu et al. 2019).”

• cites Rudnik et al. 2022Not matched

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

• cites Takemasu et al. 2019 sourceNot checked — no full text of the source

Probably not a substantial claim.

If autophagic flux is occurring, the level of LC3-II will be increased in the presence of a lysosomal degradation inhibitor because the transit of LC3-II through the autophagic pathway will be blocked.

“If autophagic flux is occurring, the level of LC3-II will be increased in the presence of a lysosomal degradation inhibitor because the transit of LC3-II through the autophagic pathway will be blocked.”

• cites Ju et al. 2010Not matched

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

• cites Klionsky et al. 2008bNot matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

mTORC1-TFEB signaling governs lysosomal biogenesis, and TFEB targets include several genes, including MCOLN1.

“mTORC1-TFEB signaling governs lysosomal biogenesis (Laplante and Sabatini 2012), (Inoki et al. 2003), (Tee et al. 2003), (Sardiello et al. 2009), (Settembre et al. 2012), (Settembre et al. 2013), (Sardiello et al. 2009), (Martina et al. 2014), and TFEB targets include several genes, including MCOLN1 (Nnah et al. 2019).”

• cites Laplante and Sabatini 2012 sourceNot checked yet
• cites Inoki et al. 2003 sourceNot checked yet
• cites Tee et al. 2003 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Autophagosomal-lysosomal dysfunction is an early feature of Alzheimer's disease (AD), preceding amyloid-β and Tau pathology.

“Autophagosomal-lysosomal dysfunction is an early feature of Alzheimer's disease (AD), preceding amyloid-β and Tau pathology (Nixon and Yang 2011).”

• cites Nixon and Yang 2011 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and dephosphorylates TFEB, thus promoting its nuclear translocation.

“Lysosomal Ca 2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and dephosphorylates TFEB, thus promoting its nuclear translocation.”

• cites Medina and Ballabio 2015Not matched

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

• cites Medina et al. 2015Not matched

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

It may state two separate claims as one.

This could probably lead to autophagic clearance defects, leading to neurodegeneration in aged and severe AD patients.

“This in turn could probably lead to autophagic clearance defects, leading to neurodegeneration in aged and severe AD patients”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

CQ disrupts SNARE-dependent membrane fusion, leading to accumulation of LC3-II-positive autophagosomes and p62, indicative of defective cargo degradation.

“CQ disrupts SNARE-dependent membrane fusion, leading to accumulation of LC3-II-positive autophagosomes and p62, indicative of defective cargo degradation (Mauthe et al. 2018).”

• cites Mauthe et al. 2018 sourceNot checked yet

Probably not a substantial claim. It may state two separate claims as one.

ChIP-seq analysis in TFEB-FLAG HeLa cells identified 46 TFEB-bound genes among 623 annotated endocytic genes, while transcriptomic profiling of TFEB-GFP-expressing HeLa cells revealed 35 endocytic genes upregulated relative to wildtype controls.

“ChIP-seq analysis in TFEB-FLAG HeLa cells identified 46 TFEB-bound genes among 623 annotated endocytic genes, while transcriptomic profiling of TFEB-GFP-expressing HeLa cells revealed 35 endocytic genes upregulated relative to wildtype controls (Nnah et al. 2019).”

• cites Nnah et al. 2019Not matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

TMEM55B is a TFEB/TFE3 target induced by starvation and cholesterol stress.

“TMEM55B is a TFEB/TFE3 target induced by starvation and cholesterol stress (Willett et al. 2017).”

• cites Willett et al. 2017 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Lysosomal Ca2+ signaling controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy.

“Ballabio, Medina and coworkers (Medina and Ballabio 2015), (Medina et al. 2015) meanwhile showed that lysosomal Ca 2+ signaling controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy.”

• cites Medina and Ballabio 2015Not matched

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

• cites Medina et al. 2015Not matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

TMEM55B was long considered a lysosomal protein of unknown function, though it regulates nuclear phosphatidylinositol-5-monophosphate.

“TMEM55B was long considered a lysosomal protein of unknown function, though it regulates nuclear phosphatidylinositol-5-monophosphate (Ungewickell et al. 2005), (Zou et al. 2007).”

• cites Ungewickell et al. 2005 sourceNot checked — no full text of the source
• cites Zou et al. 2007 sourceNot checked — no full text of the source

Probably not a substantial claim. It may be too vague to check against evidence.

These neurons could be potentially used for studying the effects of various lysosomal proteins in mediating autophagic flux to enhance clearance of Tau and other proteins known to form toxic aggregates in neurodegenerative diseases.

“These results additionally establish that these neurons could be potentially used for studying the effects of various lysosomal proteins in mediating autophagic flux to enhance clearance of Tau and other proteins known to form toxic aggregates in neurodegenerative diseases.”

It may state two separate claims as one.

Downregulation of dTMEM55 enhanced Tau-mediated neuronal degeneration, dysfunction and toxicity in fly transgenic AD models.

“All these assays, including retinal degeneration, climbing defects and lethality showed that the downregulation of dTMEM55 enhanced Tau mediated neuronal degeneration, dysfunction and toxicity in the fly transgenic AD models, indicating that these neuronal defects might lead to neurodegeneration in AD patients.”

• AssumptionRests on an assumption: The Drosophila and iPSC-derived neuron phenotypes observed are representative of human Alzheimer's disease neurodegeneration.

It may state two separate claims as one.

Downregulation of TMEM55 can potentially cause neurodegeneration in AD cases, due to lysosome transport defects, preventing the autophagic clearance of Tau.

“Overall, our data suggests that the downregulation of TMEM55 can potentially cause neurodegeneration in AD cases, due to lysosome transport defects [Schematic model, Figure 11A, 11B], preventing the autophagic clearance of Tau.”

• AssumptionRests on an assumption: The Drosophila and iPSC-derived neuron phenotypes observed are representative of human Alzheimer's disease neurodegeneration.

It may state two separate claims as one.

These findings indicate stage-specific dysregulation of TMEM55B, absent in mild or moderate AD.

“These findings indicate stage-specific dysregulation of TMEM55B, absent in mild or moderate AD.”

It may state two separate claims as one.

TMEM55B could act as a disease-severity-associated factor in neurodegeneration, indicating that lysosomal trafficking pathways may contribute to late-stage AD pathology.

“These findings suggest that TMEM55B could act as a diseaseseverity-associated factor in neurodegeneration, indicating that lysosomal trafficking pathways may contribute to late-stage AD pathology.”

It may state two separate claims as one.

TMEM55B may act as a conserved regulator of lysosomal positioning, with its downregulation potentially contributing to Tau-associated neurodegenerative processes in AD.

“Collectively, our data suggest that TMEM55B may act as a conserved regulator of lysosomal positioning, with its downregulation potentially contributing to Tauassociated neurodegenerative processes in AD.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Autophagic flux can be detected by LC3-II turnover using Western blot analysis in the presence and absence of lysosomal degradation inhibitors.

“Autophagic flux can be detected by LC3-II turnover using Western blot analysis in the presence and absence of lysosomal degradation inhibitors, such as pepstatin A, E64d, bafilomycin A1, chloroquine and NH4Cl (Ju et al. 2010), (Klionsky et al. 2008b).”

• cites Ju et al. 2010Not matched

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

• cites Klionsky et al. 2008bNot matched

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Abnormal lysosomal positioning is a hallmark of Alzheimer's disease, with lysosomes accumulating in dystrophic axons around amyloid plaques.

“Abnormal lysosomal positioning is a hallmark of Alzheimer's disease (AD), with lysosomes accumulating in dystrophic axons around amyloid plaques (Terry et al. 1964;Cataldo et al. 1994).”

• cites Terry et al. 1964Not matched

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

• cites Cataldo et al. 1994 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

If autophagic flux is occurring, the level of LC3-II will be increased in the presence of a lysosomal degradation inhibitor.

“If autophagic flux is occurring, the level of LC3-II will be increased in the presence of a lysosomal degradation inhibitor because the transit of LC3-II through the autophagic pathway will be blocked.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Early defects in autophagic flux may involve additional regulatory factors, with altered TMEM55B expression potentially contributing at later stages.

“This pattern raises the possibility that early defects in autophagic flux may involve additional regulatory factors, with altered TMEM55B expression potentially contributing at later stages.”

It may state two separate claims as one.

TMEM55B deficiency may impair retrograde lysosomal transport, potentially leading to reduced lysosomal clearance of Tau and increased neuronal vulnerability.

“Mechanistically, TMEM55B deficiency may impair retrograde lysosomal transport, potentially leading to reduced lysosomal clearance of Tau and increased neuronal vulnerability.”

It may state two separate claims as one.

TMEM55B deficiency appears to disrupt retrograde lysosomal transport, which could lead to axonal lysosome accumulation, impaired autophagic clearance, and Tau accumulation.

“TMEM55B deficiency appears to disrupt retrograde lysosomal transport, which could lead to axonal lysosome accumulation, impaired autophagic clearance, and Tau accumulation.”

It may state two separate claims as one.

TMEM55B has the potential to enhance both wild type Tau and mutant Tau P301L phenotypes in a fly AD model, an indicator of its plausible role in potentiating Tau mediated neurodegeneration in Alzheimer's Disease.

“All these results concluded, that TMEM55B had the potential to enhance both wild type Tau and mutant Tau P301L phenotypes in a fly AD model, an indicator of its plausible role in potentiating Tau mediated neurodegeneration in Alzheimer's Disease.”

• AssumptionRests on an assumption: Human TMEM55B gene shares 99% homology with Drosophila dTMEM55.

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Defects in induction, maturation, or lysosomal clearance impair protein degradation.

“Defects in induction, maturation, or lysosomal clearance impair protein degradation (Zhong et al. 2009), (Pickford et al. 2008), (Ravikumar et al. 2005), (Webb et al. 2004), (Iwata et al. 2005), (Kimura et al. 2008), (Wong and Cuervo 2010), (Lee et al. 2010), and is assessable via LC3-II turnover or p62 degradation (Mizushima et al. 2010), (Ju et al. 2010), (Klionsky et al. 2008b), (Tanida et al.”

• cites Zhong et al. 2009 sourceNot checked yet
• cites Pickford et al. 2008 sourceNot checked yet

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

• cites Ravikumar et al. 2005 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Chloroquine primarily blocks autophagic flux by impairing autophagosome-lysosome fusion through disruption of endo-lysosomal trafficking pathways and vesicular fusion machinery.

“Two landmark investigations, Mauthe et al., 2018 andNnah et al., 2019, demonstrated that CQ primarily blocks autophagic flux by impairing autophagosome-lysosome fusion through disruption of endo-lysosomal trafficking pathways and vesicular fusion machinery (Mauthe et al. 2018), (Kodani et al. 2019).”

• cites Mauthe et al. 2018 sourceNot checked yet
• cites Kodani et al. 2019 sourceNot checked yet

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

It may state two separate claims as one.

TMEM55B is lowered in aged AD neurons and not early AD neurons.

“These results indicated that TMEM55B is lowered in aged AD neurons and not the early AD neurons.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Lysosomal Ca2+ release through MCOLN1 activates calcineurin, which dephosphorylates TFEB, promoting its nuclear translocation and transcriptional activation of lysosomal and autophagic genes.

“Lysosomal Ca²⁺ release through mucolipin 1 (MCOLN1) activates calcineurin, which dephosphorylates TFEB, promoting its nuclear translocation and transcriptional activation of lysosomal and autophagic genes.”

It may state two separate claims as one.

TMEM55B expression is selectively reduced in severe AD and its loss of function exacerbates lysosomal mislocalization, impairs autophagic flux, and promotes pathological tau accumulation.

“Integrating human clinical-pathological datasets with in vivo Drosophila models and human iPSC-derived neurons, we demonstrate that TMEM55B expression is selectively reduced in severe AD and that its loss of function exacerbates lysosomal mislocalization, impairs autophagic flux, and promotes pathological tau accumulation.”

It may state two separate claims as one.

Autophagic flux defects are evident in 20-day-old neurons, whereas reductions in TMEM55B levels are detected only in 40-day-old AD neurons, suggesting a temporal separation between the onset of autophagy impairment and TMEM55B downregulation.

“The observation that autophagic flux defects are evident in 20-day-old neurons, whereas reductions in TMEM55B levels are detected only in 40-day-old AD neurons, suggests a temporal separation between the onset of autophagy impairment and TMEM55B downregulation.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Tau is a component of neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and related tauopathies.

“The microtubule-binding protein tau is a component of neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and related disorders that are collectively referred to as tauopathies (Morishima-Kawashima et al. 1995), (Johnson and Bailey 2002).”

• cites Morishima-Kawashima et al. 1995 sourceNot checked — no full text of the source
• cites Johnson and Bailey 2002 sourceNot checked — no full text of the source

It may state two separate claims as one.

The 20-day and 40-day old neurons were mature differentiated neurons and had lost stem cell potency.

“This indicated that the 20-days and 40-days old neurons were mature differentiated neurons and had lost the stem cell potency.”

It may state two separate claims as one.

Our findings indicate that the observed phenotypes are restricted to late-stage Alzheimer's disease (AD) cases, consistent with the clinical reality that early-stage AD is largely asymptomatic and lacks overt clinical manifestations.

“Our findings indicate that the observed phenotypes are restricted to late-stage Alzheimer's disease (AD) cases, consistent with the clinical reality that early-stage AD is largely asymptomatic and lacks overt clinical manifestations.”

• AssumptionRests on an assumption: Early-stage AD is largely asymptomatic and lacks overt clinical manifestations.
• AssumptionRests on an assumption: Molecular alterations are known to initiate during the early phases of the disease, but these changes often remain subtle and do not reach statistical or pathological prominence until later stages.

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Autophagic flux dysfunction contributes to AD, PD, HD, and ALS.

“Autophagic flux, encompassing autophagosome formation, maturation, lysosomal fusion, and degradation, is essential for neuronal homeostasis, and its dysfunction contributes to AD, PD, HD, and ALS (Williams et al. 2006), (Rubinsztein et al. 2007), (Wong and Cuervo 2010).”

• cites Williams et al. 2006 sourceNot checked — no full text of the source
• cites Rubinsztein et al. 2007 sourceNot checked — no full text of the source
• cites Wong and Cuervo 2010 sourceNot checked yet

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

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

In NFTs, Tau is hyperphosphorylated and tau kinases such as GSK-3β, MARK, and Cdk5 play a role in the formation of insoluble tau aggregates and NFT.

“In the NFT, Tau is hyperphosphorylated and it is widely believed that tau kinases such as glycogen synthase kinase-3β (GSK)-3β, microtubule affinity-regulating kinase (MARK) and cyclin-dependent kinase 5 (Cdk5) plays a role in the formation of insoluble tau aggregates and NFT (Cho and Johnson 2003), (Augustinack et al. 2002).”

• cites Cho and Johnson 2003 sourceNot checked — no full text of the source
• cites Augustinack et al. 2002 sourceNot checked — no full text of the source

It may state two separate claims as one.

Impaired lysosomal transport may contribute to defective autophagic flux, leading to defective clearance of protein aggregates and organelles, thereby contributing to progressive neuronal dysfunction and degeneration observed in aged and severe Alzheimer's disease patients.

“Together, these data indicate that impaired lysosomal transport may contribute to defective autophagic flux, leading to defective clearance of protein aggregates and organelles, thereby contributing to progressive neuronal dysfunction and degeneration observed in aged and severe Alzheimer's disease patients.”