Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of upper and lower motor neurons. MicroRNAs (miRNAs) are reported to be closely related to the development of ALS. However, the precise functions of miRNAs in the pathogenesis of ALS remain largely unknown. In previous studies, we determined that miRNA-193b-3p was significantly downregulated in patients with sporadic ALS (sALS). Here, we observed that miRNA-193b-3p was downregulated in the SOD1G93A mouse model of ALS and promoted cell death in NSC-34 cells. We further found that miR-193b-3p directly targeted tuberous sclerosis 1 (TSC1) to regulate mechanistic target of rapamycin complex 1 (mTORC1) activity. Downregulation of miR-193b-3p led to TSC1 increase accompanied with mTORC1 inactivation, and vice versa. Moreover, downregulation of miR-193b-3p promoted protective autophagy and cell survival in NSC-34 cells. In contrast, upregulation of miR-193b-3p activated mTORC1 signaling, leading to inhibition of autophagy and promotion of cell death. Taken together, our study suggests that downregulation of miR-193b-3p is required for cell survival by targeting TSC1/mTOR signaling in NSC-34 cells and provides a novel target for improving the clinical therapy of ALS.
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Written from the paper’s full text.
TL;DR
In NSC-34 motor neuron-like cells, miR-193b-3p directly targets TSC1 to regulate mTORC1 activity, and its downregulation increases TSC1, inactivates mTORC1, promotes autophagy, and supports cell survival. Conversely, miR-193b-3p upregulation activates mTORC1, inhibits autophagy, and promotes cell death.
Key findings
- miR-193b-3p was downregulated in the spinal cord of SOD1G93A ALS mice compared with wild-type controls at ~90 days (8 pairs of littermate mice, *P* < 0.05), and decreased further from ~90 to ~150 days.
- In NSC-34 cells, miR-193b-3p overexpression induced early/late apoptosis and decreased cell viability, while miR-193b-3p inhibition had opposite effects (3 independent experiments; *P* < 0.01 for apoptosis, *P* < 0.5 and *P* < 0.01 for viability).
- miR-193b-3p directly targeted the TSC1 3′UTR; mimics decreased TSC1 mRNA/protein and increased mTORC1 indicators pp70S6K and p4EBP1, whereas inhibitors increased TSC1 and decreased pp70S6K/p4EBP1 (4 independent experiments).
- miR-193b-3p inhibition enhanced autophagy (decreased p62, increased LC3II/I ratio, increased GFP-LC3 puncta), while mimics inhibited autophagy; in SOD1G93A spinal cord, pp70S6K and p4EBP1 were decreased and LC3 and p62 were increased (3 pairs of littermate mice).
Methods
- NSC-34 hybrid mouse motor neuron-like cells were transfected with miR-193b-3p mimics, inhibitors, or scrambled sequences; SOD1G93A transgenic mice and wild-type controls were used for spinal cord miRNA/protein analysis.
- Assays included luciferase reporter assay for TSC1 3′UTR targeting, RT-qPCR for miRNA/mRNA, western blot for TSC1/TSC2, pp70S6K, p4EBP1, p62, and LC3, CCK-8 for viability, Annexin V-FITC/PI flow cytometry for apoptosis, and GFP-LC3 puncta imaging.
- Data were presented as mean ± SEM from at least three independent experiments and analyzed by two-tailed unpaired Student’s *t* test or ANOVA with LSD post-test; significance levels were 0.05 (*), 0.01 (), and 0.001 (*).
Limitations
- The paper states that further longitudinal study in ALS patients will be helpful to confirm these results, and that the contribution of autophagy to ALS pathology remains controversial and not fully elucidated.
- Evident from the text: the functional experiments are largely limited to NSC-34 cells in vitro and SOD1G93A mouse tissue, with no direct manipulation of miR-193b-3p in human ALS samples in this study.
- Evident from the text: some mouse analyses use small sample sizes (e.g., 8 pairs for miRNA expression and 3 pairs for spinal cord western blots), and the study does not report in vivo miR-193b-3p manipulation.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
19 of 42 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Autophagy protects cells from death, especially motor neurons.
“Autophagy could protect cells from death (Hara et al., 2006; Komatsu et al., 2006), especially in the case of motor neurons (Barmada et al., 2014).”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
mTORC1 is a key regulator of autophagy inhibition.
“Notably, mTORC1 has been identified as a key regulator of autophagy inhibition (Kim et al., 2011).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Kim et al., 2011 source
- Findingcitation
miR-193b-3p is downregulated in ALS patients.
“In this study, we tried to clarify whether miR-193b-3p, a downregulated miRNA in ALS patients reported in our previous study (Chen et al., 2016), involves in cell survival by targeting TSC1/mTOR signaling in autophagy (Figure 6).”
- Also stated in: § Discussion · boosted
“Our findings confirmed that miR-193b-3p is downregulated in ALS patients and mouse models, accompanied by decreased mTORC1 activity.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Chen et al., 2016 source
The Discussion reports lower hsa-miR-193b expression in leukocytes from Chinese patients with sporadic ALS than in healthy controls. Our copy does not identify the measured miRNA as the specific 3p form, so it supports the downregulation finding but not that added specificity. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Also stated in: § Discussion · boosted
- Premisecitation
Autophagy could protect cells from death, especially in motor neurons.
“Autophagy could protect cells from death (Hara et al., 2006; Komatsu et al., 2006), especially in motor neurons (Barmada et al., 2014).”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
mTOR is a negative regulator of autophagy.
“mTOR is widely accepted as a negative regulator of autophagy (Kim et al., 2011).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Kim et al., 2011 source
- Premisecitation
Autophagy is protective for neuronal survival in neurodegenerative diseases.
“Autophagy is now recognized as protective for neuronal survival in neurodegenerative diseases (Hara et al., 2006; Komatsu et al., 2006; Lee, 2012).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Hara et al., 2006 source
- cites Komatsu et al., 2006 source
- cites Lee, 2012 source
The Conclusion and Perspectives section says neuronal autophagy can protect cells under disease conditions, supporting its protective role. But it also says excessive autophagy or defective autophagic flux can contribute to neurodegeneration and neuronal death, so the unqualified claim overstates the review's context-dependent account. The supplied passages do not specify page numbers. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
SOD1 mutants render vulnerable motor neurons dependent on endogenous neuroprotection signaling involving mTOR.
“SOD1 mutants specifically render vulnerable motor neurons dependent on endogenous neuroprotection signaling involving excitability and mechanistic target of rapamycin (mTOR; Leibinger et al., 2012; Saxena et al., 2013).”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
Autophagy seems to be protective for the survival of motor neurons in ALS.
“Therefore, autophagy seems to be protective for the survival of motor neurons in ALS.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Crippa et al., 2010 source
The Introduction (p. 2) describes HspB8-mediated autophagic removal of neurotoxic mutant SOD1 as a possible protective mechanism in ALS. The paper also observes autophagy in surviving motor neurons (p. 9), but its cell-viability tests found no survival difference (p. 7); it does not establish that autophagy protects motor-neuron survival. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
TSC1 is a potential candidate target of miR-193b-3p in NSC-34 cells based on sequence analysis.
“The results showed that TSC1, a well-known regulator of mTORC1 signaling was a potential candidate of miR-193b-3p in NSC-34 cells (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p mimics decrease GFP-LC3 puncta formation in NSC-34 cells.
“Images showed that miR-193b-3p inhibitors dramatically increased the formation of GFP-LC3 puncta, whereas miR-193b-3p mimics decreased the formation of GFP-LC3 puncta (Figure 5C).”
Quote in the paperSubstantial claim - Findingreasoning
miR-193b-3p directly targets TSC1.
“In this study, we obtained evidence that miR-193b-3p targets the upstream factor of mTOR (TSC1) to counteract the effect of miR-193a.”
- Also stated in: § Discussion · hedged
“Therefore, we propose that these effects may be beneficial for the precise regulation of mTOR signaling, and miR-193b-3p directly targets TSC1 and modulates mTOR activity.”
- Also stated in: § Discussion · hedged
“In conclusion, our results suggest that miR-193b-3p directly targets TSC1 to regulate mTORC1 activity.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Findingown data
miR-193b-3p mimics increase p62 protein expression in NSC-34 cells.
“We also found that miR-193b-3p mimics increased p62 protein expression and decreased the ratio of LC3II/I in NSC-34 cells (Figures 5A,B, and Supplementary Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
Torin1 blocks miR-193b-3p mimic-induced phosphorylation of p70S6K and 4EBP1 in NSC-34 cells.
“The results showed that Torin1 could block the miR-193b-3p mimic-induced phosphorylation of p70S6K and 4EBP1”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p inhibitors dramatically increase GFP-LC3 puncta formation in NSC-34 cells.
“Images showed that miR-193b-3p inhibitors dramatically increased the formation of GFP-LC3 puncta, whereas miR-193b-3p mimics decreased the formation of GFP-LC3 puncta (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
pp70S6K and p4EBP1 are decreased in the spinal cord of SOD1G93A mutant mice compared with controls.
“pp70S6K and p4EBP1, two important indicators of mTORC1 signaling, were both decreased in the spinal cord of SOD1G93A mutant mice compared with controls”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p inhibition enhances autophagy in NSC-34 cells, indicated by decreased p62 and increased LC3II/I ratio.
“The results showed that miR-193b-3p inhibition enhanced autophagy (indicated by decreased p62 and increased ratio of LC3II/I) in NSC-34 cells.”
Quote in the paperSubstantial claim - Findingown data
Autophagy is activated in the spinal cord of SOD1G93A mutant mice, as indicated by increased LC3 and p62.
“We also noted that autophagy was activated in the spinal cord of SOD1G93A mutant mice, as indicated by the increase of autophagy markers LC3 and p62 (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p decreases in the spinal cord of ALS mice from approximately 90 days to approximately 150 days.
“We also noted that miR-193b-3p was decreased in the spinal cord of ALS mice from ~90 days to ~150 days (Supplementary Figure S1A).”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p mimics decrease the LC3II/I ratio in NSC-34 cells.
“We also found that miR-193b-3p mimics increased p62 protein expression and decreased the ratio of LC3II/I in NSC-34 cells (Figures 5A,B, and Supplementary Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p is downregulated in the spinal cord of SOD1G93A ALS mice compared with wild-type controls at approximately 90 days.
“The results showed that the expression of miR-193b-3p was also downregulated in the spinal cord of SOD1G93A ALS mice compared with wild-type controls (~90 days; Figure 1A).”
- Also stated in: § Abstract · plain
“miRNA-193b-3p was downregulated in the SOD1G93A mouse model of ALS”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingreasoning
mTORC1 activity is decreased in ALS patients and mouse models.
“Our findings confirmed that miR-193b-3p is downregulated in ALS patients and mouse models, accompanied by decreased mTORC1 activity.”
Quote in the paperSubstantial claim - Findingown data
miR-193b-3p is downregulated in mouse models of ALS.
“Our findings confirmed that miR-193b-3p is downregulated in ALS patients and mouse models, accompanied by decreased mTORC1 activity.”
Quote in the paperSubstantial claim - Interpretationown data
miR-193b-3p mimics increase p70S6K and 4EBP1 phosphorylation in an mTOR-dependent manner.
“suggesting that miR-193b-3p mimics increase p70S6K and 4EBP1 phosphorylation in an mTOR-dependent manner (Supplementary Figure S2A).”
Quote in the paperSubstantial claim - Interpretationown data
Upregulation of miR-193b-3p promotes cell death in NSC-34 cells.
“Therefore, we propose that upregulation of miR-193b-3p could promote cell death in NSC-34 cells.”
- Also stated in: § Abstract · plain
“promoted cell death in NSC-34 cells”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Premisecitation
mTORC1 signaling inhibits the cellular catabolism of autophagy.
“However, mTORC1 signaling coordinately activates anabolic processes, such as protein synthesis, while inhibiting the cellular catabolism of autophagy (Chan, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chan, 2009 source
- Interpretationreasoning
miR-193b-3p modulates mTOR activity.
“Therefore, we propose that these effects may be beneficial for the precise regulation of mTOR signaling, and miR-193b-3p directly targets TSC1 and modulates mTOR activity.”
Quote in the paperSubstantial claim - Interpretationown data
miR-193b-3p counteracts the effect of miR-193a.
“In this study, we obtained evidence that miR-193b-3p targets the upstream factor of mTOR (TSC1) to counteract the effect of miR-193a.”
Quote in the paperSubstantial claim - Interpretationown data
miR-193b-3p negatively regulates autophagy in NSC-34 cells.
“Taken together, these results indicate that miR-193b-3p negatively regulates autophagy in NSC-34 cells.”
Quote in the paperSubstantial claim - Interpretationown data
miR-193b-3p targets TSC1 to control mTOR signaling.
“Therefore, we propose that miR-193b-3p indeed targets TSC1 to control mTOR signaling.”
Quote in the paperSubstantial claim - Interpretationreasoning
Downregulation of miR-193b-3p is required for cell survival by targeting TSC1/mTOR signaling in NSC-34 cells.
“our study suggests that downregulation of miR-193b-3p is required for cell survival by targeting TSC1/mTOR signaling in NSC-34 cells”
- Also stated in: § Introduction · hedged
“Our work suggests that downregulation of miR-193b-3p is required for cell survival by targeting TSC1/mTOR signaling to promote autophagy.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · hedged
- Interpretationreasoning
The study provides a novel target for improving the clinical therapy of ALS.
“provides a novel target for improving the clinical therapy of ALS.”
- Also stated in: § Introduction · hedged
“These findings may inform novel therapeutic targets for ALS.”
Quote in the paperNot a substantial claim- Rests on an assumption: NSC-34 cells are a valid model for motor neurons in ALS, such that findings in NSC-34 cells about miR-193b-3p, TSC1/mTOR, autophagy, and cell survival reflect ALS motor neuron biology.
- Rests on an assumption: The SOD1G93A mouse model's miR-193b-3p and mTORC1/autophagy changes are representative of human ALS.
- Also stated in: § Introduction · hedged
- Premisecitation
Many studies in cellular and animal models of ALS indicate enhanced autophagy activity in ALS.
“Many studies in cellular and animal models of ALS indicate enhanced autophagy activity in ALS (Morimoto et al., 2007; Sasaki, 2011), in addition to the occurrence of autophagy-mediated clearance of mutant SOD1 and TDP-43 (Nassif et al., 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
These results reveal potential roles of miR-193b-3p in cell death of motor neurons in the development of ALS.
“These results at least reveal potential roles of miR-193b-3p in cell death of motor neurons in the development of ALS.”
Quote in the paperSubstantial claim - Interpretationown data
miR-193b-3p regulates autophagy for cell survival in NSC-34 cells through TSC1/mTOR.
“We found that miR-193b-3p regulates autophagy for cell survival in NSC-34 cells through TSC1/mTOR.”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibition of miR-193b-3p may protect cells from death.
“Inhibition of miR-193b-3p downregulates mTOR activity and activates autophagy, which may protect cells from death.”
Quote in the paperSubstantial claim - Interpretationreasoning
Increased miR-193b-3p activates mTORC1 signaling.
“Increased miR-193b-3p activates mTORC1 signaling, inhibits autophagy and thus promotes cell death.”
Quote in the paperSubstantial claim - Interpretationreasoning
The co-reduction of miR-193b-3p and mTORC1 activity promotes autophagy to protect cells from death.
“The co-reduction of miR-193b-3p and mTORC1 activity promotes autophagy to protect cells from death.”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibition of miR-193b-3p downregulates mTOR activity.
“Inhibition of miR-193b-3p downregulates mTOR activity and activates autophagy, which may protect cells from death.”
Quote in the paperSubstantial claim - Premisecitation
The number of autophagic vacuoles is significantly increased in the motor neurons of the spinal cords of SOD1G93A mice compared with controls.
“For example, the number of autophagic vacuoles is significantly increased in the motor neurons of the spinal cords of SOD1G93A mice compared with controls (Massey et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Massey et al., 2006 source
- Interpretationreasoning
Inhibition of miR-193b-3p activates autophagy.
“Inhibition of miR-193b-3p downregulates mTOR activity and activates autophagy, which may protect cells from death.”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibition of miR-193b-3p leads to mTORC1 inactivation.
“Inhibition of miR-193b-3p leads to increased TSC1 and mTORC1 inactivation.”
Quote in the paperSubstantial claim - Interpretationreasoning
The effect of miR-193b-3p on TSC1/mTOR signaling is fundamentally important to cell survival in ALS development.
“Therefore, we propose that the effect of miR-193b-3p on TSC1/mTOR signaling is fundamentally important to cell survival in ALS development.”
Quote in the paperSubstantial claim - Interpretationreasoning
Increased miR-193b-3p inhibits autophagy.
“Increased miR-193b-3p activates mTORC1 signaling, inhibits autophagy and thus promotes cell death.”
Quote in the paperSubstantial claim - Interpretationreasoning
mTORC1 activity should be downregulated in ALS to meet the demand of increased autophagy.
“Therefore, it is predicted that mechanistic target of rapamycin (mTORC1) activity should be downregulated in ALS to meet the demand of increased autophagy.”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibition of miR-193b-3p leads to increased TSC1.
“Inhibition of miR-193b-3p leads to increased TSC1 and mTORC1 inactivation.”
Quote in the paperSubstantial claim - Interpretationreasoning
Increased miR-193b-3p promotes cell death.
“Increased miR-193b-3p activates mTORC1 signaling, inhibits autophagy and thus promotes cell death.”
Quote in the paperSubstantial claim
- May combine two claims. 14
- Classified as probably not a substantial claim. 18
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationmiR-193b-3p was downregulated in sporadic ALS patients and provided high diagnostic accuracy for sporadic ALS.
“We noted that miR-193b-3p was downregulated in sALS patients and provided high diagnostic accuracy for sALS (Chen et al., 2016).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Chen et al., 2016 source
The Discussion reports that hsa-miR-193b was downregulated in sporadic ALS patients relative to healthy controls. But the paper does not identify the measured form as miR-193b-3p, and its reported AUCs for miR-193b (0.713 in the Results and 0.62 in the Discussion) do not support describing its individual diagnostic accuracy as high. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeletion of TSC1 potently enhances axon regeneration.
“Genetic and pharmacological evidence has shown that deletion of TSC1, a negative regulator of mTOR signaling, led to constitutive activation of mTOR, neuroprotective effects and potently enhanced axon regeneration (Park et al., 2008).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Park et al., 2008 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmTOR activity in motor neurons influences the progression rates of motor dysfunction, muscle denervation and cell death in fALS.
“Moreover, mTOR activity in motor neurons influenced the progression rates of motor dysfunction, muscle denervation and cell death, suggesting that mTOR signaling is required for endogenous neuroprotection to counteract disease progression in fALS (Saxena et al., 2013).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Saxena et al., 2013 source
Classified as probably not a substantial claim.
PremisecitationDeletion of TSC1 leads to constitutive activation of mTOR.
“Genetic and pharmacological evidence has shown that deletion of TSC1, a negative regulator of mTOR signaling, led to constitutive activation of mTOR, neuroprotective effects and potently enhanced axon regeneration (Park et al., 2008).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Park et al., 2008 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiRNAs play an important role in neurodegenerative diseases, including ALS.
“Growing evidence suggests that miRNAs play an important role in neurodegenerative diseases, including ALS (Akerblom et al., 2012; Goodall et al., 2013; Zhu et al., 2013; Parisi et al., 2016).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Akerblom et al., 2012 source
The Introduction and Discussion describe miR-124’s role in neuronal differentiation and neurogenesis, not in neurodegenerative disease. Searches for ALS, amyotrophic lateral sclerosis, neurodegenerative disease, and pathology found no passage connecting miRNAs to ALS or neurodegenerative diseases in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites Goodall et al., 2013 source
- cites Zhu et al., 2013 source
The Discussion (page unavailable) says there is growing recognition that miRNAs play a prominent role in neurological and muscular disease. The Results also demonstrate miRNA effects on motor-nerve-terminal function, but the passages found do not address ALS specifically. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationThe tuberous sclerosis tumor suppressor complex, composed of TSC1 and TSC2, negatively regulates mTORC1 activity.
“The tuberous sclerosis tumor suppressor complex (TSC), composed of TSC1 and TSC2, negatively regulates mTORC1 activity (Yang et al., 2016).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Yang et al., 2016 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeletion of TSC1 has neuroprotective effects.
“Genetic and pharmacological evidence has shown that deletion of TSC1, a negative regulator of mTOR signaling, led to constitutive activation of mTOR, neuroprotective effects and potently enhanced axon regeneration (Park et al., 2008).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Park et al., 2008 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmTOR signaling is required for endogenous neuroprotection to counteract disease progression in fALS.
“Moreover, mTOR activity in motor neurons influenced the progression rates of motor dysfunction, muscle denervation and cell death, suggesting that mTOR signaling is required for endogenous neuroprotection to counteract disease progression in fALS (Saxena et al., 2013).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Saxena et al., 2013 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDefects in autophagic flux or specific autophagy-regulatory processes, rather than simple induction of autophagy, may contribute to motor neuron degeneration.
“Studies suggest that defects in autophagic flux or specific autophagy-regulatory processes, rather than simple induction of autophagy, may contribute to motor neuron degeneration (Banerjee et al., 2010).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Banerjee et al., 2010 source
The quote only partly states this claim.
Findingown datamiR-193b-3p directly targets TSC1 via binding sites within the TSC1 3'UTR to regulate mTORC1 activity.
“miR-193b-3p directly targeted tuberous sclerosis 1 (TSC1) to regulate mechanistic target of rapamycin complex 1 (mTORC1) activity.”
- Also stated in: § miR-193b-3p Directly Targets TSC1 and Regulates mTORC1 Activity in NSC-34 Cells · boosted
“By luciferase reporter assay, we confirmed the targeting sites of miR-193b-3p within TSC1 (Figure 3B).”
Quote in the paperSubstantial claim- Also stated in: § miR-193b-3p Directly Targets TSC1 and Regulates mTORC1 Activity in NSC-34 Cells · boosted
May combine two claims.
Findingown datamiR-193b-3p overexpression decreases TSC1 mRNA expression and its inhibition increases it in NSC-34 cells.
“qRT-PCR results showed that the relative expression of TSC1 was dramatically decreased by miR-193b-3p overexpression (mimics) and increased by its inhibition (inhibitors; Figure 3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCell viability is decreased by miR-193b-3p overexpression and increased by its inhibition in NSC-34 cells.
“The results showed that cell viability was decreased by miR-193b-3p overexpression and increased by its inhibition (Figure 2C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-193b-3p mimics reduce TSC1 protein levels and inhibitors induce them in NSC-34 cells.
“Western blot results showed that the protein level of TSC1 was dramatically reduced by miR-193b-3p mimics and induced by its inhibitors (Figures 4A,B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDownregulation of miR-193b-3p promotes protective autophagy and cell survival in NSC-34 cells.
“Moreover, downregulation of miR-193b-3p promoted protective autophagy and cell survival in NSC-34 cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDownregulation of miR-193b-3p leads to TSC1 increase accompanied by mTORC1 inactivation, and vice versa.
“Downregulation of miR-193b-3p led to TSC1 increase accompanied with mTORC1 inactivation, and vice versa.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-193b-3p mimics increase mTORC1 signaling indicators pp70S6K and p4EBP1, while inhibitors decrease them in NSC-34 cells.
“Consistently, the indicators of mTORC1 signaling, pp70S6K and p4EBP1, were both increased by miR-193b-3p mimics and decreased by its inhibitors (Figures 4A,C,D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn TSC1 knockdown NSC-34 cells, miR-193b-3p inhibitors neither increase TSC1 protein nor decrease mTORC1 activity.
“The results showed that miR-193b-3p inhibitors could neither increase TSC1 protein nor decrease mTORC1 activity in TSC1 knockdown cells (Supplementary Figure S2B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-193b-3p overexpression induces early and late apoptosis in NSC-34 cells, while its inhibition has opposite effects.
“The results showed that miR-193b-3p overexpression induced either early or late apoptosis in NSC-34 cells, while its inhibition exhibited opposite effects (Figures 2A,B).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAutophagy may play key roles in the etiology of neurodegenerative diseases.
“Currently, accumulating evidence suggests that autophagy is deregulated in neurodegenerative diseases and may play key roles in the etiology of these pathologies (Rubinsztein, 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rubinsztein, 2006 source
May combine two claims.
InterpretationreasoningDownregulation of miR-193b-3p is required for cell survival by improving autophagy through the TSC1/mTOR pathway.
“Our findings suggest that downregulation of miR-193b-3p is required for cell survival and provide novel molecular mechanisms for the detection and treatment of ALS.”
- Also stated in: § Discussion · hedged
“Taken together, our work supports the hypothesis that miR-193b-3p decrease is required for cell survival by improving autophagy through the TSC1/mTOR pathway and might inform the development of early therapeutic strategies in ALS.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · hedged
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApproximately 20% of familial ALS and 5% of sporadic ALS cases are caused by mutations in the SOD1 gene.
“Approximately 20% of fALS and 5% of sALS cases are caused by mutations in the SOD1 gene (Majoor-Krakauer et al., 2003; Robberecht and Philips, 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNSC-34 is a hybrid motor neuron-like cell line produced by the fusion of neuroblastoma with mouse motor neuron-enriched primary spinal cord cells.
“NSC-34 is a hybrid motor neuron-like cell line produced by the fusion of neuroblastoma with mouse motor neuron-enriched primary spinal cord cells (Eggett et al., 2000; Matusica et al., 2008; Maier et al., 2013), and it is widely used in studies of ALS in vitro.”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationmTORC1 signaling activates anabolic processes such as protein synthesis.
“However, mTORC1 signaling coordinately activates anabolic processes, such as protein synthesis, while inhibiting the cellular catabolism of autophagy (Chan, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chan, 2009 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationERBB4 and S6K2 are direct targets of miR-193a-3p in non-small-cell lung cancer.
“It has been reported that ERBB4 and S6K2 are the direct targets of miR-193a-3p and that PIK3R3 and mTOR are the direct targets of miR-193a-5p in non-small-cell lung cancer (Yu et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yu et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown datamiR-193b-3p is a positive regulator of mTORC1 signaling and directly targets TSC1 to control mTORC1 activity in NSC-34 cells.
“Taken together, our data revealed that miR-193b-3p was a positive regulator of mTORC1 signaling and directly targeted TSC1 to control mTORC1 activity in NSC-34 cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiRNA-193a-3p and miRNA-193a-5p directly target and downregulate the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway.
“Interestingly, miRNA-193a-3p and miRNA-193a-5p could directly target and downregulate the ERBB4/PIK3R3/mTOR/ S6K2 signaling pathway (Yu et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yu et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPIK3R3 and mTOR are direct targets of miR-193a-5p in non-small-cell lung cancer.
“It has been reported that ERBB4 and S6K2 are the direct targets of miR-193a-3p and that PIK3R3 and mTOR are the direct targets of miR-193a-5p in non-small-cell lung cancer (Yu et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yu et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataUpregulation of miR-193b-3p activates mTORC1 signaling, leading to inhibition of autophagy and promotion of cell death.
“In contrast, upregulation of miR-193b-3p activated mTORC1 signaling, leading to inhibition of autophagy and promotion of cell death.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAutophagy is deregulated in neurodegenerative diseases.
“Currently, accumulating evidence suggests that autophagy is deregulated in neurodegenerative diseases and may play key roles in the etiology of these pathologies (Rubinsztein, 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rubinsztein, 2006 source
May combine two claims.
Study design and conductown dataTransfection with miR-193b-3p mimics induces miR-193b-3p expression and inhibitors block it in NSC-34 cells.
“qRT-PCR results showed that the expression of miR-193b-3p was dramatically induced by miR-193b-3p mimics and significantly blocked by its inhibitors (Figure 1C).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAutophagy-mediated clearance of mutant SOD1 and TDP-43 occurs.
“Many studies in cellular and animal models of ALS indicate enhanced autophagy activity in ALS (Morimoto et al., 2007; Sasaki, 2011), in addition to the occurrence of autophagy-mediated clearance of mutant SOD1 and TDP-43 (Nassif et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nassif et al., 2010 source
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenDownregulation of miR-193b-3p could be a potential biomarker for the detection of ALS development.
“Moreover, the downregulation of miR-193b-3p could be a potential biomarker for the detection of ALS development.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
NSC-34 cells are a valid model for motor neurons in ALS, such that findings in NSC-34 cells about miR-193b-3p, TSC1/mTOR, autophagy, and cell survival reflect ALS motor neuron biology.
“we used NSC-34 cells to investigate the fundamental functions of miR-193b-3p in the development of ALS.”
“NSC-34 hybrid mouse motor neuron-like cells”
The paper relies on this without support.
The SOD1G93A mouse model's miR-193b-3p and mTORC1/autophagy changes are representative of human ALS.
“we further examined the expression of miR-193b-3p in the SOD1G93A ALS mouse model”
“SOD1G93A transgenic mice were purchased from the Jackson Lab (Bar Harbor, ME, USA).”
The paper relies on this without support.
It is still unknown how alterations of specific miRNAs contribute to the development of ALS.
“Despite these findings, it is still unknown how alterations of specific miRNAs contribute to the development of ALS.”
The paper relies on this without support.
The contribution of autophagy to the pathology of ALS has not yet been fully elucidated.
“However, the contribution of autophagy to the pathology of ALS has not yet been fully elucidated.”
The paper relies on this without support.
It remains controversial whether activating autophagy is beneficial or detrimental for motor neuron degeneration.
“Although autophagic alteration has been confirmed in ALS patients and experimental models, it remains controversial whether activating autophagy is beneficial or detrimental for motor neuron degeneration.”
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.
Figure captions use a different threshold for * significance
MinorThe statistical methods define * as the 0.05 significance level, but several figure captions define it as P < 0.5. These are different thresholds for the same symbol.
“*P < 0.5 and **P < 0.01 vs. control.”
“the values 0.05 (*), 0.01 (**) and 0.001 (***) were assumed as the level of significance for the statistic tests carried out.”
Mutant luciferase reporter is named both pMUT and pMT
MinorThe methods name the mutant TSC1 reporter pMUT, then call the mutant reporter used in the control transfections pMT without defining a separate pMT construct.
“the reconstituted plasmid was named pMUT.”
“miR-193b-3p mimics and pMT, or miRNA negative control (miR-NC) and pWT, or miR-NC and pMT were also transfected into NSC-34 cells as controls.”
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BackgroundOnset and Progression in Inherited ALS Determined by Motor Neurons and Microglia
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BackgroundThe changing scene of amyotrophic lateral sclerosis
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Immunoregulatory functions of mTOR inhibition
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“Excessive cellular stress causes progressive damage to motor neurons (Turner and Atkin, 2006; Barber and Shaw, 2010).”
BackgroundNeuroblastoma × spinal cord (NSC) hybrid cell lines resemble developing motor neurons
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BackgroundOxidative stress in ALS: Key role in motor neuron injury and therapeutic target
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BackgroundAutophagy induction enhances TDP43 turnover and survival in neuronal ALS models
Barmada, S. J., Serio, A., Arjun, A., Bilican, B., Daub, A., Ando, D. M., Tsvetkov, A., Pleiss, M., Li, X., Peisach, D., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1563 · Cited by 431 · cited 4× · see citing works
“, 2006), especially in motor neurons (Barmada et al., 2014).”
BackgroundInfluentialT lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS
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“Moreover, some studies report that autophagic clearance of mutant SOD1 exert protective effect against motor neuron loss in an ALS mouse model (Crippa et al., 2010).”
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“Moreover, some studies report that autophagic clearance of mutant SOD1 exert protective effect against motor neuron loss in an ALS mouse model (Crippa et al., 2010).”
BackgroundIs SOD1 loss of function involved in amyotrophic lateral sclerosis?
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“Aberrant misfolded proteins resulting from SOD1 mutation contribute to increased cellular stress and axon degeneration (Wilcox et al., 2009; Saccon et al., 2013).”
BackgroundChaperone-mediated autophagy in aging and disease
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“Interestingly, miRNA-193a-3p and miRNA-193a-5p could directly target and downregulate the ERBB4/PIK3R3/mTOR/ S6K2 signaling pathway (Yu et al., 2015).”
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“To confirm the pathogenic role of downregulation of miR-193b-3p in ALS, we further examined the expression of miR-193b-3p in the SOD1G93A ALS mouse model (Ferrante et al., 1997; Chiu et al., 2008).”
BackgroundAutophagy in Spinal Cord Motor Neurons in Sporadic Amyotrophic Lateral Sclerosis
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“Many studies in cellular and animal models of ALS indicate enhanced autophagy activity in ALS (Morimoto et al., 2007; Sasaki, 2011), in addition to the occurrence of autophagymediated clearance of mutant SOD1 and TDP-43 (Nassif et al., 2010).”
BackgroundFUS stimulates microRNA biogenesis by facilitating co‐transcriptional Drosha recruitment
Morlando, M., Modigliani, S. D., Torrelli, G., Rosa, A., Carlo, V. D., Caffarelli, E., & Bozzoni, I. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.319 · Cited by 229 · cited 1× · see citing works
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Increased autophagy in transgenic mice with a G93A mutant SOD1 gene
Morimoto, N., Nagai, M., Ohta, Y., Miyazaki, K., Kurata, T., Morimoto, M., Murakami, T., Takehisa, Y., Ikeda, Y., Kamiya, T., et al. (2007) · Brain Research · doi:10.1016/j.brainres.2007.06.045 · Cited by 223 · cited 1× · see citing works
“Many studies in cellular and animal models of ALS indicate enhanced autophagy activity in ALS (Morimoto et al., 2007; Sasaki, 2011), in addition to the occurrence of autophagymediated clearance of mutant SOD1 and TDP-43 (Nassif et al., 2010).”
BackgroundmTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex
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“In a previous study, we demonstrated that miR-193b-3p was downregulated and might be a candidate miRNA in the pathogenesis of ALS (Chen et al., 2016).”
BackgroundInfluentialMicroRNA-124 is a subventricular zone neuronal fate determinant
Akerblom, M., Sachdeva, R., Barde, I., Verp, S., Gentner, B., Trono, D., & Jakobsson, J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0558-12.2012 · Cited by 207 · cited 1× · see citing works
“Growing evidence suggests that miRNAs play an important role in neurodegenerative diseases, including ALS (Akerblom et al., 2012; Goodall et al., 2013; Zhu et al., 2013; Parisi et al., 2016).”
BackgroundAutophagy in the physiology and pathology of the central nervous system
Nikoletopoulou, V., Papandreou, M. E., & Tavernarakis, N. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.204 · Cited by 206 · cited 1× · see citing works
“Once neurons encounter stress, they develop multiple cellular processes to resist these pressures, such as autophagy (Nikoletopoulou et al., 2015).”
BackgroundAutophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications
Banerjee, R., Beal, M. F., & Thomas, B. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.09.001 · Cited by 199 · cited 2× · see citing works
“Autophagy is now recognized as an arbiter of neuronal survival and death decisions in neurodegenerative diseases (Banerjee et al., 2010).”
BackgroundNeuronal dark matter: the emerging role of microRNAs in neurodegeneration
Goodall, E. F., Heath, P. R., Bandmann, O., Kirby, J., & Shaw, P. J. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00178 · Cited by 187 · cited 1× · see citing works
“Growing evidence suggests that miRNAs play an important role in neurodegenerative diseases, including ALS (Akerblom et al., 2012; Goodall et al., 2013; Zhu et al., 2013; Parisi et al., 2016).”
BackgroundTowards a neuroimaging biomarker for amyotrophic lateral sclerosis
Turner, M. R., Großkreutz, J., Kassubek, J., Abrahams, S., Agosta, F., Benatar, M. G., Filippi, M., Goldstein, L. H., van den Heuvel, M. P., Kalra, S., et al. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70049-7 · Cited by 171 · cited 1× · see citing works
“…dismutase (SOD1; Rosen et al., 1993), TAR DNA-binding protein (TARDBP) which encodes TDP43 (Sreedharan et al., 2008), and fused in sarcoma (FUS; Vance et al., 2009) have been shown to be involved in Abbreviations: ALS, amyotrophic lateral sclerosis; C9orf72, chromosome 9 open reading frame 72;…”
BackgroundCaccamo, A., Majumder, S., Deng, J. J., Bai, Y., Thornton, F. B., & Oddo, S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.031278 · Cited by 169 · cited 1× · see citing works
“In ALS, defective autophagy has also been implicated in the accumulation of ubiquitinated TDP-43 inclusions and motor neuron degeneration (Caccamo et al., 2009).”
BackgroundGenetic epidemiology of amyotrophic lateral sclerosis
Majoor‐Krakauer, D., Willems, P., & Hofman, A. (2003) · Clinical Genetics · doi:10.1046/j.0009-9163.2002.00001.x · Cited by 147 · cited 1× · see citing works
“Approximately 20% of fALS and 5% of sALS cases are caused by mutations in the SOD1 gene (Majoor-Krakauer et al., 2003; Robberecht and Philips, 2013).”
BackgroundTNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy
Matsuzawa, Y., Oshima, S., Takahara, M., Maeyashiki, C., Nemoto, Y., Kobayashi, M., Nibe, Y., Nozaki, K., Nagaishi, T., Okamoto, R., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1055439 · Cited by 138 · see citing works
Modifications of Superoxide Dismutase (SOD1) in Human Erythrocytes
Wilcox, K. C., Zhou, L., Jordon, J. K., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809687200 · Cited by 131 · cited 1× · see citing works
“Aberrant misfolded proteins resulting from SOD1 mutation contribute to increased cellular stress and axon degeneration (Wilcox et al., 2009; Saccon et al., 2013).”
BackgroundSelf-citationMicroRNA-125b regulates microglia activation and motor neuron death in ALS
Parisi, C., Napoli, G., Amadio, S., Spalloni, A., Apolloni, S., Longone, P., & Volonté, C. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.153 · Cited by 127 · cited 1× · see citing works
“Growing evidence suggests that miRNAs play an important role in neurodegenerative diseases, including ALS (Akerblom et al., 2012; Goodall et al., 2013; Zhu et al., 2013; Parisi et al., 2016).”
BackgroundNeuronal autophagy: a housekeeper or a fighter in neuronal cell survival?
Lee, J.-A. (2012) · Experimental Neurobiology · doi:10.5607/en.2012.21.1.1 · Cited by 119 · cited 1× · see citing works
“Autophagy is now recognized as protective for neuronal survival in neurodegenerative diseases (Hara et al., 2006; Komatsu et al., 2006; Lee, 2012).”
BackgroundDevelopment and characterisation of a glutamate-sensitive motor neurone cell line
Eggett, C. J., Crosier, S., Manning, P., Cookson, M. R., Menzies, F. M., McNeil, C. J., & Shaw, P. J. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0741895.x · Cited by 111 · cited 1× · see citing works
“NSC-34 is a hybrid motor neuron-like cell line produced by the fusion of neuroblastoma with mouse motor neuron-enriched primary spinal cord cells (Eggett et al., 2000; Matusica et al., 2008; Maier et al., 2013), and it is widely used in studies of ALS in vitro.”
BackgroundDifferentiated NSC-34 motoneuron-like cells as experimental model for cholinergic neurodegeneration
Maier, O., Böhm, J., Dahm, M., Brück, S., Beyer, C., & Johann, S. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.03.008 · Cited by 108 · cited 1× · see citing works
“NSC-34 is a hybrid motor neuron-like cell line produced by the fusion of neuroblastoma with mouse motor neuron-enriched primary spinal cord cells (Eggett et al., 2000; Matusica et al., 2008; Maier et al., 2013), and it is widely used in studies of ALS in vitro.”
BackgroundRole of mTOR in neuroprotection and axon regeneration after inflammatory stimulation
Leibinger, M., Andreadaki, A., & Fischer, D. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.01.004 · Cited by 89 · cited 1× · see citing works
“…render vulnerable motor neurons dependent on endogenous neuroprotection signaling involving excitability and mechanistic target of rapamycin (mTOR; Leibinger et al., 2012; Saxena et al., 2013). mTOR signaling senses extracellular stimuli and regulates many biological processes, such as cell…”
BackgroundNK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation
Yang, M., Chen, S., Du, J., He, J., Wang, Y., Li, Z., Liu, G., Peng, W., Zeng, X., Li, D., et al. (2016) · Nature Communications · doi:10.1038/ncomms12730 · Cited by 73 · cited 1× · see citing works
“The tuberous sclerosis tumor suppressor complex (TSC), composed of TSC1 and TSC2, negatively regulates mTORC1 activity (Yang et al., 2016).”
BackgroundAberration of miRNAs expression in leukocytes from sporadic amyotrophic lateral sclerosis
Chen, Y., Wei, Q., Chen, X., Li, C., Cao, B., Ou, R., Hadano, S., & Shang, H.-F. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00069 · Cited by 69 · cited 1× · see citing works
“To confirm the pathogenic role of downregulation of miR-193b-3p in ALS, we further examined the expression of miR-193b-3p in the SOD1G93A ALS mouse model (Ferrante et al., 1997; Chiu et al., 2008).”
BackgroundSelf-citationCharacterization and use of the NSC-34 cell line for study of neurotrophin receptor trafficking
Matusica, D., Fenech, M. P., Rogers, M., & Rush, R. A. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21507 · Cited by 67 · cited 1× · see citing works
“NSC-34 is a hybrid motor neuron-like cell line produced by the fusion of neuroblastoma with mouse motor neuron-enriched primary spinal cord cells (Eggett et al., 2000; Matusica et al., 2008; Maier et al., 2013), and it is widely used in studies of ALS in vitro.”
BackgroundNovoselov, S. S., Mustill, W. J., Gray, A. L., Dick, J. R. T., Kanuga, N., Kalmár, B., Greensmith, L., & Cheetham, M. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073944 · Cited by 63 · cited 1× · see citing works
“Accordingly, the neuronal defensive system must be evoked to protect neurons from death (Novoselov et al., 2013; Wang et al., 2015).”
BackgroundTDP-43 Regulates the Microprocessor Complex Activity During In Vitro Neuronal Differentiation
Carlo, V. D., Grossi, E., Laneve, P., Morlando, M., Modigliani, S. D., Ballarino, M., Bozzoni, I., & Caffarelli, E. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8564-x · Cited by 63 · cited 1× · see citing works
“Furthermore, mutations of TARDBP and FUS in ALS, both of which are closely related to miRNA processing, give rise to more links between ALS and miRNAs (Morlando et al., 2012; Di Carlo et al., 2013).”
BackgroundAmyotrophic lateral sclerosis pathogenesis: a journey through the secretory pathway
Nassif, M., Matus, S., Castillo, K., & Hetz, C. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2991 · Cited by 60 · cited 2× · see citing works
“Many studies in cellular and animal models of ALS indicate enhanced autophagy activity in ALS (Morimoto et al., 2007; Sasaki, 2011), in addition to the occurrence of autophagymediated clearance of mutant SOD1 and TDP-43 (Nassif et al., 2010).”
BackgroundER Stress and UPR in Familial Amyotrophic Lateral Sclerosis
Turner, B. J., & Atkin, J. D. (2006) · Current Molecular Medicine · doi:10.2174/156652406775574550 · Cited by 59 · see citing works
Wang, S., Ren, M., Jiang, H., Wang, J., Jiang, H.-Q., Yin, X. L., Qi, Y., Wang, X.-D., Dong, G.-T., Wang, T., et al. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.06.002 · Cited by 31 · cited 1× · see citing works
“Aberrant misfolded proteins resulting from SOD1 mutation contribute to increased cellular stress and axon degeneration (Wilcox et al., 2009; Saccon et al., 2013).”
BackgroundZhu, H., Bhattacharyya, B. J., Lin, H., & Gomez, C. M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.0224-13.2013 · Cited by 26 · cited 1× · see citing works
“Growing evidence suggests that miRNAs play an important role in neurodegenerative diseases, including ALS (Akerblom et al., 2012; Goodall et al., 2013; Zhu et al., 2013; Parisi et al., 2016).”
BackgroundHushing mTOR boosts immunity to pathogens
Bordon, Y. (2013) · Nature reviews. Immunology · doi:10.1038/nri3562 · Cited by 7 · cited 2× · see citing works
“…stimuli and regulates many biological processes, such as cell growth, energy metabolism and autophagy (Thomson et al., 2009; Laplante and Sabatini, 2012). mTOR is a PI3K-like serine/threonine protein kinase that is evolutionarily conserved in all eukaryotes (Dazert and Hall, 2011; Bordon, 2013).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Autophagy and apoptosis cascade: which is more prominent in neuronal death?
Gupta, R. V., Ambasta, R. K., & Kumar, P. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04004-4 · Cited by 171 · see citing works
Salama, R. M., Abdel‐Latif, G. A., Abbas, S. S., Magdoub, H. M. E., & Schaalan, M. F. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107900 · Cited by 147 · see citing works
Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex
Fay, M. J., Alt, L., Ryba, D., Salamah, R., Peach, R., Papaeliou, A., Zawadzka, S., Weiss, A. S., Patel, N., Rahman, A., et al. (2018) · Toxics · doi:10.3390/toxics6010016 · Cited by 94 · see citing works
“miRNA-193b-3p was found to be downregulated in the renal cortices from Cd-treated animals, and downregulation of this miRNA has been shown to promote autophagy and cell survival in mouse motor neuron-like cells [61].”
BackgroundMicroRNAs as major regulators of the autophagy pathway
Akkoç, Y., & Gözüaçık, D. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118662 · Cited by 85 · see citing works
The role of microRNAs in diseases and related signaling pathways
Vaghf, A., Khansarinejad, B., Ghaznavi‐Rad, E., & Mondanizadeh, M. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06725-y · Cited by 51 · see citing works
The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis
Liu, J., Zhou, F., Guan, Y., Meng, F., Zhao, Z., Su, Q., Bao, W., Wang, X., Zhao, J., Huo, Z., et al. (2022) · Cells · doi:10.3390/cells11030572 · Cited by 49 · see citing works
“It might provide a key target of early therapeutic strategies in ALS [82].”
BackgroundSelf-citationDifferential plasma microvesicle and brain profiles of microRNA in experimental cerebral malaria
Cohen, A., Zinger, A., Tiberti, N., Grau, G. E., & Combes, V. (2018) · Malaria Journal · doi:10.1186/s12936-018-2330-5 · Cited by 47 · see citing works
“Specifically, miR-193b is decreased in abundance in amyotrophic lateral sclerosis [58], and in sepsis [59], for which it has been identified as a biomarker.”
MicroRNA-193b-3p regulates hepatocyte apoptosis in selenium-deficient broilers by targeting MAML1
Liu, T., Yang, T., Xu, Z., Tan, S., Pan, T., Wan, N., & Li, S. (2018) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2018.06.013 · Cited by 44 · see citing works
Azam, H. M. H., Rößling, R., Geithe, C., Khan, M. M., Dinter, F., Hanack, K., Prüß, H., Husse, B., Roggenbuck, D., Schierack, P., et al. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1386735 · Cited by 45 · see citing works
“The study found that miR-183b-5p targets RIP kinase 1 (RIPK) and programmed cell death 4 (PDCD4), indicating its role in programmed neuronal cell death (Li C. et al., 2017).”
BackgroundRole of TSC1 in physiology and diseases
Mallela, K., & Kumar, A. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04088-3 · Cited by 40 · see citing works
Shah, S. Z. A., Zhao, D., Hussain, T. A., Sabir, N., & Yang, L. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00139 · Cited by 40 · see citing works
“Li et al. (2017) demonstrated that miRNA-193b-3p plays a vital role in the pathogenesis of ALS.”
BackgroundMORC4 is a novel breast cancer oncogene regulated by miR‐193b‐3p
Yang, Z., Zhuang, Q., Hu, G., & Geng, S. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27751 · Cited by 39 · see citing works
Li, C., Wei, Q., Gu, X., Chen, Y., Chen, X., Cao, B., Ou, R., & Shang, H. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00114 · Cited by 39 · see citing works
“RNA Extraction and Real-Time Quantitative PCR Assay The total RNA extraction and real-time quantitative PCR (RT-qPCR) for mRNA and miRNA were performed following standard procedures as previously described (Li et al., 2017).”
MethodSelf-citationMicroRNA Cues from Nature: A Roadmap to Decipher and Combat Challenges in Human Health and Disease?
Singh, G., & Storey, K. B. (2021) · Cells · doi:10.3390/cells10123374 · Cited by 40 · see citing works
Li, C., Chen, Y., Chen, X., Wei, Q., Ou, R., Gu, X., Cao, B., & Shang, H. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15490 · Cited by 38 · see citing works
Self-citationRNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective
Laneve, P., Tollis, P., & Caffarelli, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910285 · Cited by 32 · see citing works
Effects of exosomal miRNAs in the diagnosis and treatment of Alzheimer’s disease
Cui, G.-H., Zhu, J., Wang, Y., Wu, J., Liu, J., & Guo, H.-D. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111593 · Cited by 32 · see citing works
Systematic review and meta-analysis on microRNAs in amyotrophic lateral sclerosis
Liu, H., Lan, S., Shi, X., Fan, F.-C., Liu, Q., Cong, L., & Cheng, Y. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.01.005 · Cited by 31 · see citing works
Wang, L., & Zhang, L. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04773-z · Cited by 26 · see citing works
Diagnostic Circulating miRNAs in Sporadic Amyotrophic Lateral Sclerosis
Panio, A., Cava, C., D’Antona, S., Bertoli, G. R., & Porro, D. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.861960 · Cited by 24 · see citing works
Qi, R., Zhang, X., Xie, Y., Jiang, S., Liu, Y., Liu, X., Xie, W., Jia, X., Bade, R., Shi, R., et al. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109219 · Cited by 21 · see citing works
Cheng, Y., Gu, X., Yang, T., Wei, Q., Cao, B., Zhang, Y., Shang, H., & Chen, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1106497 · Cited by 22 · see citing works
“, 2020) and miR-193b-3p (Li et al., 2017) were involved in the neurodegeneration by functional investigations.”
BackgroundSelf-citationGenomic and transcriptomic advances in amyotrophic lateral sclerosis
Rizzuti, M., Sali, L., Melzi, V., Scarcella, S., Costamagna, G., Ottoboni, L., Quetti, L., Brambilla, L., Papadimitriou, D. A., Verde, F., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102126 · Cited by 22 · see citing works
MicroRNA-23a-3p Is Upregulated in Plasma Exosomes of Bulbar-onset ALS Patients and Targets ERBB4
Liu, Y., Ding, M., Pan, S., Zhou, R., Yao, J., Fu, R., Yu, H., & Lu, Z. (2023) · Neuroscience · doi:10.1016/j.neuroscience.2023.05.030 · Cited by 18 · see citing works
Niccolini, B., Palmieri, V., Spirito, M. D., & Papi, M. (2021) · Materials · doi:10.3390/ma15010126 · Cited by 16 · see citing works
“Its downregulation stimulates cell death by targeting tuberous sclerosis 1 [47], which controls rapamycin complex 1, a regulator of autophagy, and a neuroprotector [66,67].”
BackgroundWe, Z., Yang, Y., Xiang, Z., Cheng, J., Yu, Z., Wang, W., Hu, L., Ma, F., Deng, Y., Jin, Z., et al. (2022) · Aging · doi:10.18632/aging.203883 · Cited by 17 · see citing works
Oncogenic role of MiR-130a in oral squamous cell carcinoma
Mallela, K., Swamy, S. S., Gopinath, K. S., & Kumar, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-87388-4 · Cited by 15 · see citing works
Koike, Y. M., & Onodera, O. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1131758 · Cited by 13 · see citing works
“Since miR-193b-3p downregulates autophagy mechanism, reducing this miRNA is required for cell survival by promoting autophagy through TSC1-mTORC1 pathway (Li et al., 2017).”
BackgroundNeto, J. R. M., de Souza, G. F., dos Santos, V. M., et al. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05067-1 · Cited by 11 · see citing works
Xu, H., Zhang, T., Hu, X., et al. (2021) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-021-00596-0 · Cited by 10 · see citing works
Cross‐Ethnic Variant Screening and Burden Analysis of PTPA in Parkinson's Disease
Li, C., Lin, J., Jiang, Q., et al. (2023) · Movement Disorders · doi:10.1002/mds.29411 · Cited by 8 · see citing works
“Total RNA extraction, reverse-transcription polymerase chain reaction (RT-PCR), and quantitative PCR (qPCR) for mRNA were performed following standard protocols as described previously.(15) The primer for mRNA was as shown below.”
MethodSelf-citationGenetic Determinants of Survival in Parkinson's Disease in the Asian Population
Li, C., Hou, Y., Ou, R., Gu, X., Chen, Y., Zhang, L., Liu, K., Lin, J., Cao, B., Wei, Q., et al. (2022) · Movement Disorders · doi:10.1002/mds.29069 · Cited by 8 · see citing works
“After transfection for 48 hours, the cells were fixed with 4% paraformaldehyde, mounted on cover glasses with Prolong Gold antifade reagent with DAPI, and visualized using a Nikon Ni-E microscope, as described previously.(29)”
MethodSelf-citationHuang, J., Yu, Y., Pang, D., Li, C., Wei, Q., Cheng, Y., Cui, Y., Ou, R., & Shang, H. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03835-5 · Cited by 7 · see citing works
Self-citationTsamou, M., Carpi, D., Pistollato, F., & Roggen, E. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215434 · Cited by 6 · see citing works
The Role of Non-Coding RNAs in ALS
Falduti, A., Giovinazzo, A., Feudo, E. L., Rocca, V., Brighina, F., Messina, A. A., Conforti, F. L., & Iuliano, R. (2025) · Genes · doi:10.3390/genes16060623 · Cited by 5 · see citing works
“Therefore, the inhibition of miR-125b reduces NF-kB expression and protects motor neurons from death [73].”
Satarug, S. (2019) · MDPI eBooks · doi:10.3390/books978-3-03897-985-2 · Cited by 5 · see citing works
Higashi, S., Yamakuchi, M., Hashinokuchi, H., Takenouchi, K., Tabaru, A., Oyama, Y., Fujisaki, C., Tanoue, K., & Hashiguchi, T. (2025) · PLoS ONE · doi:10.1371/journal.pone.0318811 · Cited by 5 · see citing works
Fan, Q., Bao, X., Zhao, H. Q., & Li, S. (2024) · 3 Biotech · doi:10.1007/s13205-024-03975-y · Cited by 2 · see citing works
“…pathway, contributing significantly to various cellular processes such as development, cell growth, proliferation, survival, autophagy, and ciliary development through its collaboration with a diverse array of regulatory molecules (Huang and Manning 2008; Li et al. 2017; Mallela and Kumar 2021).”
The role of microRNAs on autophagy in cervical cancer: review
Asfaw, M. S., & Kassahun, W. D. (2025) · Discover Oncology · doi:10.1007/s12672-025-04284-3 · Cited by 2 · see citing works
Amelkina, O., da Silva, A. M., Silva, A. R., & Comizzoli, P. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1009220 · Cited by 3 · see citing works
“study on hibernating grey mouse lemurs reported increased expression of miRNAs miR-92a and miR-193b during torpor, which was related to regulation of p53 signaling and mTOR pathway (Li et al., 2017; Biggar et al., 2018; Zhang et al., 2020).”
BackgroundSaini, S., Medda, N., Pramanik, S. D., Pathak, T., & Roy, P. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-19084-1.00005-3 · Cited by 2 · see citing works
miR-514a promotes neuronal development in human iPSC-derived neurons
Akaba, Y., Takahashi, S., Suzuki, K., et al. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1096463 · Cited by 1 · see citing works
“, 2016) and downregulation of miR193b-3p promotes autophagy and cell survival by targeting TSC1/ mTOR signaling (Li et al., 2017).”
BackgroundMicroRNAs Regulating Autophagy in Neurodegeneration
Lai, Q., Kovzel, N., Konovalov, R., & Vinnikov, I. A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-16-2830-6_11 · Cited by 1 · see citing works
Noncoding RNAs regulating serine/threonine kinases in neurodegeneration
Khamineh, Y., Ghiasvand, M., Zolghadri, S., & Saboury, A. A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-44173-8.00007-3
MicroRNAs modulate cell death mechanisms in neurodegenerative disorders
Singh, A., Subramanian, M., & Singh, A. (2026) · Aging advances. · doi:10.4103/agingadv.agingadv-d-26-00023
- Authors
- Li, C., Chen, Y., Chen, X., Wei, Q., Cao, B., & Shang, H.
- Affiliations
- Sichuan University (CN)
- Corresponding author
- Shang, HuiFang
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2017-05-30
- Volume
- 10
- Pages
- 160-160
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC5447700
- OpenAlex
- W2619434486
- Semantic Scholar
- 971780180d406ca48e8762dbfd3240562948d856
- Cited by
- 45
- References
- 60
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 9 · 2022: 6 · 2021: 10 · 2020: 3 · 2019: 4 · 2018: 5
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Key Research and Development Program of China
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- amyotrophic lateral sclerosis, mTORC1, autophagy, cell survival, SOD1 G93A mouse model, NSC-34 cells, microRNA downregulation
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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