The DOI matches its Crossref record; 79 of the 83 references it cites were found in a registry or an index; 20 of the 43 sources its claims cite were checked for support.
Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
Open accessAbstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.
Overview
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Written from the paper’s full text.
TL;DR
The paper reports reduced retromer cargo-recognition core proteins in ALS models and human ALS motor neurons, and identifies compound 2a, a phenyl bis-guanylhydrazone, as a retromer stabilizer that increases VPS35/VPS26 levels. In SOD1G93A mice, compound 2a attenuated motor impairment, increased motor neuron survival, and reduced axonal degeneration and protein aggregation.
Key findings
- VPS35, VPS26b, and VPS29 were reduced in lumbar spinal cords of SOD1G93A mice; VPS35 reduction was significant at day 20 (p = 0.007), day 60 (p = 0.0015), and day 90 (p < 0.0001), while VPS26b (p = 0.002) and VPS29 (p = 0.0019) were reduced at day 100. Vps35, Vps26, and Vps29 mRNA levels did not drop significantly.
- Compound 2a was selected from docking at the VPS35-VPS29 interface with calculated Kd = 1.8 µM and normalized Kd = 0.53 µM (35/40 poses); it increased VPS35 in Neuro2a cells, showed brain bioavailability, had an LD50 of ∼260 µM, and bound the VPS29-VPS35 heterodimer by STD-NMR and WaterLOGSY-NMR.
- In SOD1G93A mice, compound 2a (10 mg/kg i.p. daily) slowed motor deficits (rotarod day 90 p = 0.0041; day 100 p = 0.0006), increased motor neuron survival (NeuN p = 0.002; ChAT p = 0.043), reduced degenerating sciatic nerve fibers by ∼30% (p = 0.02), and increased VPS35, VPS26, CI-MPR, Sortilin, and mature CTSD levels.
- Compound 2a reduced poly-ubiquitinated proteins and high-molecular-weight SOD1G93A aggregates in G93A mice; in human ALS postmortem motor neurons and SOD1-mutant iPSC-derived motor neurons, VPS35/VPS26 were reduced, and compound 2a increased VPS35 in ALS iPSC-derived motor neurons (WB p = 0.017).
Methods
- In silico docking used AutoDock4.2 with the VPS29-VPS35 heterodimer (PDB 2R17), 40 independent runs per compound, and a normalized Kd weighting recurrence; compounds were synthesized and characterized by NMR, including STD-NMR and WaterLOGSY.
- In vitro work used Neuro2a cells, primary mouse cortical neurons on microelectrode arrays, SOD1G93A transfection, VPS35 knockdown/overexpression, cycloheximide chase, viability/LDH assays, immunoblotting, and confocal imaging.
- In vivo work used SOD1G93A and C57BL/6J mice treated with compound 2a (10 mg/kg i.p. daily from day 30 to 100 or day 83 to 103), with rotarod testing, histology/immunofluorescence, immunoblotting, blue-native PAGE, and mass spectrometry brain pharmacokinetics; human samples included ALS and control postmortem spinal cords and iPSC-derived motor neurons from SOD1 fALS patients and healthy volunteers.
Limitations
- The paper states that it cannot rule out compound 2a modulating additional targets other than the CRC, that further experiments with VPS35 conditional knockout mice are needed to validate the in vivo mechanism, that CTSD inactivation experiments are needed to investigate its contribution, and that mechanisms linking retromer stabilization to Golgi rescue and to retromer failure in ALS remain unknown.
- Evident from the text: some in vivo and human analyses rely on small samples or single experiments, such as ChAT quantification (n = 3–4 mice, one experiment), iPSC compound 2a WB (n = 3 wells, one experiment), and human postmortem analysis (four non-neurological controls and five ALS biopsies).
- Evident from the text: the study reports motor, histological, and biochemical outcomes but does not report survival or lifespan extension in the ALS mice.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
20 of 43 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured
- Premisecitation
R55/1 binds to a characterized hot spot at the interface between VPS35 and VPS29.
“R55/1 binds to a characterized hot spot at the interface between VPS35 and VPS2920.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014). source
- Premisecitation
Lysosome impairment is among the earliest pathological events that affect MNs in G93A mice.
“Remarkably, lysosome impairment is among the earliest pathological events that affect MNs in G93A mice7.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Xie, Y. et al. Endolysosomal deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS mice. Neuron 87, 355–370 (2015). source
- Findingown data
Poly-ubiquitinated protein levels are doubled in Neuro2a cells receiving a VPS35-targeted RNAi.
“We next assessed that poly-ubiquitinated protein levels were doubled in Neuro2a cells receiving a VPS35-targeted RNAi, suggesting that loss of retromer functionality alters lysosomal homeostasis and the accumulation of poly-ubiquitinated proteins (Supplementary Fig. 12d, e)21.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Seaman, M. N. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004). source
The Methods describe mVPS26 siRNA in HeLaM cells, and the supplemental-material description reports effects of mVPS35 knockdown on trafficking, not poly-ubiquitinated proteins. A search for Neuro2a cells, poly-ubiquitination, and doubled protein levels found no passage in our copy reporting the claimed result. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Findingown data
Compound 2a increases retromer stability in ALS mice.
“while increasing retromer stability in ALS mice”
Quote in the paperSubstantial claim - Findingown data
VPS35 mean fluorescence intensity levels are significantly reduced in motor neurons of vehicle-treated G93A mice.
“We observed a significant reduction of VPS35 mean fluorescence intensity (MFI) levels in vehicle-treated G93A mice.”
Quote in the paperSubstantial claim
- Findingown data
G93A mice receiving compound 2a from postnatal day 83 to day 103 display a general attenuation of motor deficits.
“As expected, mice receiving compound 2a displayed a general attenuation of motor deficits (Supplementary Fig. 13a).”
Quote in the paperSubstantial claim - Findingown data
Many motor neurons from vehicle-treated G93A mice display a reduction of GM130-covered areas.
“We observed that many MNs from vehicle-treated G93A mice displayed a reduction of GM130-covered areas, possibly indicating the organelle fragmentation55 (Fig. 7e).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Mourelatos, Z., Gonatas, N. K., Stieber, A., Gurney, M. E. & Dal Canto, M. C. The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc. Natl Acad. Sci. USA 93, 5472–5477 (1996). source
- Findingown data
Compound 2a preserves myelin integrity in G93A mice.
“Parallel sections, labelled for myelin basic protein (MBP) and medium neurofilaments (NF-M), showed deranged myelin in vehicle-treated G93A mice while compound 2a treatment preserved the integrity of myelin in G93A mice (Supplementary Fig. 9e).”
Quote in the paperSubstantial claim - Findingown data
VPS35 protein levels are significantly reduced in motor neurons of SOD1G93A mice.
“We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice.”
- Also stated in: § CRC proteins are downregulated in G93A mice · plain
“VPS35 immunoreactivity was substantially attenuated in MNs of asymptomatic and symptomatic G93A mice (Fig. 1a and Supplementary Fig. 1b, c).”
- Also stated in: § CRC proteins are downregulated in G93A mice · plain
“We observed a significant reduction of VPS35 in asymptomatic and symptomatic G93A mice, as well as a reduction of VPS26b and VPS29 in symptomatic G93A mice (Fig. 1c–e and Supplementary Fig. 1g, h).”
Quote in the paperSubstantial claim - Also stated in: § CRC proteins are downregulated in G93A mice · plain
- Findingown data
VPS35 is reduced in iPSC-derived motor neurons from ALS patients.
“We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice.”
Quote in the paperSubstantial claim - Findingown data
VPS26 immunoreactivity is substantially reduced in ALS samples.
“Parallel sections probed for VPS26 revealed a substantial reduction of VPS26 immunoreactivity in ALS samples (Fig. 8c, d).”
Quote in the paperSubstantial claim - Findingown data
CI-MPR mean fluorescence intensity levels significantly increase in compound 2a-treated G93A motor neurons.
“However, MFI levels significantly increased in compound 2a-treated G93A MNs (Fig. 6c).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a treatment significantly reverts the enlarged lysosome phenotype in Neuro2a cells expressing SOD1G93A.
“After 24 h of starvation, cells receiving only SOD1G93A plasmids showed enlarged lysosomes, while as expected treatment with compound 2a significantly reverted this phenotype (Supplementary Fig. 12f, g).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of VPS35 reverts the reduced viability of SOD1G93A-transfected Neuro2a cells.
“However, this phenotype was reverted co-transfecting VPS35 and SOD1G93A plasmids (Fig. 3c).”
Quote in the paperSubstantial claim - Findingown data
CI-MPR mean fluorescence intensity levels are substantially reduced in motor neurons of vehicle-treated G93A mice compared with WT litters.
“we observed a substantial reduction of CI-MPR MFI levels in MNs of vehicle-treated G93A mice compared with WT litters (Fig. 6c).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a increases VPS35 levels in Neuro2a cells.
“Similarly, compounds 2a, 3a, and 4a increased VPS35 levels, while compound 5a did not (Fig. 2f).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a binds to the VPS29-VPS35 heterodimer.
“The STD-NMR spectrum (Fig. 2i) shows the aromatic signals of compound 2a in presence of the VPS29-VPS35 heterodimer, strongly indicating an interaction between the ligand and the protein complex.”
- Also stated in: § NMR studies · hedged
“indicating that 2a binds to the protein complex”
- Also stated in: § Discussion · boosted
“Through STD-NMR and WL-NMR experiments we experimentally proved the binding of 2a to the VPS29-VPS35 heterodimer.”
Quote in the paperSubstantial claim - Also stated in: § NMR studies · hedged
- Findingown data
The intensity of high molecular weight SOD1 entities is lowered in G93A mice treated with compound 2a.
“The intensity of such high MW entities was lowered in G93A mice treated with compound 2a (Supplementary Fig. 13b, c).”
Quote in the paperSubstantial claim - Findingown data
VPS26 mean fluorescence intensity levels are significantly increased in compound 2a-treated G93A mice.
“As expected, MFI levels were reduced in vehicle-treated G93A mice, while they were significantly increased in compound 2a-treated mice (Fig. 6b).”
Quote in the paperSubstantial claim - Findingown data
Sortilin mean fluorescence intensity levels are significantly reduced in motor neurons of vehicle-treated G93A mice.
“Sortilin MFI levels were significantly reduced in MNs of vehicle-treated G93A mice, while significantly increased by compound 2a (Fig. 6d).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a restores cell viability in SOD1G93A-transfected Neuro2a cells.
“Notably, cell viability was restored in SOD1G93A-transfected and compound 2a-treated Neuro2a cells (Fig. 3b).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a increases VPS35 in iPSC-derived motor neurons.
“compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability.”
Quote in the paperSubstantial claim - Findingown data
VPS35 and VPS26 immunoreactivities are not altered in NeuN+ cells in the motor cortex of G93A mice.
“Conversely, we did not find alterations of VPS35 and VPS26 immunoreactivities in NeuN+ cells sampled in the motor cortex of G93A mice (Supplementary Fig. 2a–f).”
Quote in the paperNot a substantial claim - Findingown data
In G93A mice, compound 2a treatment (10 mg/kg, day 100) reduces the density of degenerating fibers in sciatic nerve cross sections compared with vehicle.
“Quantifications (means + SD) of degenerating fibers/mm2 scored in the entire cross section of nerves are shown in d, and data are examined over two independent experiments (WT n = 7 independent mice, G93A-vehicle n = 8 independent mice, G93A-compound 2a n = 9 independent mice).(G93A-v vs. G93A-2a: p = 0.02.”
Quote in the paperSubstantial claim - Findingown data
VPS26b and VPS29 protein levels are reduced in symptomatic G93A mice.
“We observed a significant reduction of VPS35 in asymptomatic and symptomatic G93A mice, as well as a reduction of VPS26b and VPS29 in symptomatic G93A mice (Fig. 1c–e and Supplementary Fig. 1g, h).”
Quote in the paperSubstantial claim - Findingown data
VPS35 levels in ISLET1+ motor neurons are reduced in ALS samples.
“Using immunofluorescence and WBs, we observed that VPS35 levels in ISLET1+ MNs were reduced in ALS samples (Fig. 8e, f).”
Quote in the paperSubstantial claim - Findingown data
VPS35 interference by Sh56 in Neuro2a cells results in enlarged and abnormally distributed lysosomes.
“We observed enlarged and abnormally distributed lysosomes in cells with VPS35 interference by Sh56 (Supplementary Fig. 12a–c).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a increases motor neuron survival in ventral horns of spinal cords of G93A mice.
“Histopathological analysis of lumbar SCs showed more MNs in ventral horns of SCs from compound 2a-treated G93A mice than from vehicle-treated G93A mice (Fig. 4d, e).”
- Also stated in: § Abstract · plain
“compound 2a attenuates locomotion impairment and increases MNs survival.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Compound 2a substantially attenuates Golgi fragmentation in SOD1G93A overexpressing cells and in G93A mice.
“Using compound 2a we observed a substantial attenuation of Golgi fragmentation in SOD1G93A overexpressing cells and in G93A mice.”
Quote in the paperSubstantial claim - Findingown data
Ubiquitin mean fluorescence intensity levels in ventral horn motor neurons are higher in vehicle-treated G93A mice than in compound 2a-treated G93A mice.
“MFI levels of ubiquitin fluorescence in vehicle-treated G93A MNs were higher than in compound 2a-treated G93A mice, further confirming previous results53 (Fig. 7c and d).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Saxena, S., Cabuy, E. & Caroni, P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat. Neurosci. 12, 627–636 (2009). source
- Findingown data
Sortilin mean fluorescence intensity levels are significantly increased by compound 2a in G93A mice.
“Sortilin MFI levels were significantly reduced in MNs of vehicle-treated G93A mice, while significantly increased by compound 2a (Fig. 6d).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a increases VPS26b and VPS29 protein levels in Neuro2a cells after 48 h.
“Accordingly, VPS26b and VPS29 proteins were significantly increased by compound 2a in Neuro2a cells after treatment for 48 h (Supplementary Fig. 5a).”
Quote in the paperSubstantial claim - Findingnone given
The retromer alteration occurs early in G93A mice.
“This alteration occurs early in G93A mice, suggesting that the retromer could be an early therapeutic target in ALS, albeit future investigations are needed to identify mechanisms leading to retromer failure in ALS MNs.”
Quote in the paperSubstantial claim - Findingown data
VPS35 immunoreactivity is substantially reduced in motor neurons of ALS patients.
“VPS35 immunoreactivity was substantially reduced in ALS MNs, confirming our observations in G93A mice (Fig. 8b).”
Quote in the paperSubstantial claim - Findingown data
Levels of mature CTSD significantly increase in compound 2a-treated G93A mice.
“However, levels of mature CTSD significantly increased in compound 2a-treated G93A mice (Fig. 6e).”
Quote in the paperSubstantial claim - Findingown data
VPS35, VPS26, and VPS29 mRNA levels in lumbar spinal cord extracts of G93A mice do not drop significantly compared with WT controls.
“Despite the reduction of VPS protein levels, their mRNA levels did not drop significantly when compared with WT controls, suggesting that their reduction was not caused by transcriptional inhibition (Fig. 1f).”
Quote in the paperNot a substantial claim - Findingown data
Compound 2a reduces demyelination in G93A mice.
“Compound 2a-treated G93A mice displayed a substantial reduction of demyelination when compared with vehicle-treated G93A mice (Supplementary Fig. 9a–d).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a modestly increases viability of SOD1G93A-Sh56 double transfected cells.
“Notably, incubation of SOD1G93A-Sh56 double transfected cells with compound 2a modestly increased cell viability, confirming that compound 2a counteracts SOD1G93A-mediated cytotoxicity by increasing VPS35 levels and retromer functionality.”
Quote in the paperSubstantial claim - Findingown data
VPS35 knockdown worsens the reduced viability of SOD1G93A-transfected Neuro2a cells.
“By including Sh56 plasmids in the transfection mix, we worsened this phenotype (Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
ALS 27 cells display fewer VPS35+ puncta than control cells.
“ALS 27 cells displayed less VPS35+ puncta than controls, albeit both cell types significantly increased VPS35+ puncta when treated with compound 2a (Fig. 8g).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a significantly reduces LDH release in SOD1G93A-transfected Neuro2a cells.
“Compound 2a significantly reduced LDH release in cells transfected with SOD1G93A, while LDH increased when cells received SOD1G93A and Sh56 plasmids.”
Quote in the paperSubstantial claim - Findingown data
Compound 2a protects VPS35 from degradation in Neuro2a cells.
“Conversely, pretreating cells with compound 2a protected VPS35 from degradation (Supplementary Fig. 6a, b).”
Quote in the paperSubstantial claim - Findingown data
Neuro2a cells receiving only SOD1G93A plasmids show enlarged lysosomes after 24 h of starvation.
“After 24 h of starvation, cells receiving only SOD1G93A plasmids showed enlarged lysosomes, while as expected treatment with compound 2a significantly reverted this phenotype (Supplementary Fig. 12f, g).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a accesses the CNS in C57BL6J mice.
“Pharmacokinetic analysis of C57BL6J brains receiving daily intraperitoneal injections of compound 2a confirmed its access to the CNS (Fig. 2h).”
- Also stated in: § Abstract · plain
“compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Compound 2a has a calculated Kd of 1.8 μM and normalized Kd of 0.53 μM (35/40 poses) for the VPS35-VPS29 interface.
“When phenyl and 1,3 guanylhydrazones were introduced in compound 2a (gray in Fig. 2e and Supplementary Fig. 4b, e–g), it displayed a favorable orientation with the phenyl ring filling surface recess 1, further increasing affinity for the putative binding site (calculated Kd = 1.8 µM) with high recurrence (normalized Kd = 0.53 µM-35/40 poses).”
Quote in the paperNot a substantial claim - Findingown data
VPS26 mean fluorescence intensity levels are reduced in vehicle-treated G93A mice.
“As expected, MFI levels were reduced in vehicle-treated G93A mice, while they were significantly increased in compound 2a-treated mice (Fig. 6b).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a slows progression of motor deficits in G93A mice.
“Strikingly, the progression of motor deficits in G93A mice was significantly slowed down by compound 2a (Fig. 4c).”
- Also stated in: § Abstract · plain
“compound 2a attenuates locomotion impairment and increases MNs survival.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
The mature CTSD/pro-CTSD ratio is slightly but not significantly reduced in spinal cord extracts of vehicle-treated G93A mice compared with WT litters.
“We observed a slight, but not significant reduction of the mature CTSD/pro-CTSD ratio in SC extracts of vehicle-treated G93A mice compared with WT litters.”
Quote in the paperNot a substantial claim - Findingown data
Compound 2a significantly reverts trans-Golgi fragmentation in SOD1G93A-transfected Neuro2a cells.
“Compound 2a significantly reverted this phenotype (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a reduces degenerating fibers in sciatic nerves of G93A mice by ~30%.
“Conversely, mice treated with compound 2a showed a ∼30% reduction of degenerating fibers (Fig. 5c, d).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a substantially reduces poly-ubiquitinated protein levels in G93A mice.
“Vehicle-treated G93A mice displayed abundant poly-ubiquitinated proteins whereas their levels were substantially reduced by compound 2a (Fig. 7b).”
Quote in the paperSubstantial claim - Findingown data
The reduction of GM130-covered areas in G93A motor neurons is substantially reverted by compound 2a treatment.
“However, this phenomenon was substantially reverted when we scored MNs of compound 2a-treated G93A mice (Fig. 7e).”
Quote in the paperSubstantial claim - Findingown data
The calculated LD50 of compound 2a in Neuro2a cells is ~260 μM.
“The calculated LD50 was ∼260 µM (Fig. 2m), a higher value than the concentration needed to stabilize the retromer in vitro.”
Quote in the paperSubstantial claim - Findingown data
VPS26 immunoreactivity is attenuated in spinal cord sections of G93A mice.
“Similarly, we observed attenuated VPS26 immunoreactivity in parallel SC sections (Fig. 1b and Supplementary Fig. 1d–f).”
Quote in the paperSubstantial claim - Findingown data
Compound 2a does not alter locomotion performances in WT mice.
“We did not observe alterations of locomotion performances in WT mice treated with compound 2a (Fig. 4b).”
Quote in the paperNot a substantial claim - Findingown data
Compound 2a does not influence transcription levels of CRC genes in Neuro2a cells.
“Compound 2a, as R55/120, did not influence the transcription levels of CRC genes in Neuro2a cells, as determined by measuring Vps35, Vps26, and Vps29 mRNAs levels by real-time PCR (Supplementary Fig. 6c).”
Quote in the paperNot a substantial claim - Findingown data
Compound 2a significantly increases VPS35 levels in spinal cord extracts of C57BL6J mice.
“While treatment with isothiourea 4a slightly, but not significantly, increased VPS35 levels, phenyl-1,3-guanylhydrazone 2a significantly increased VPS35 levels in SC extracts (Fig. 2g).”
Quote in the paperSubstantial claim - Findingown data
Western blots of lumbar spinal cord extracts confirm that compound 2a increases VPS35 and VPS26b levels in G93A mice.
“WBs of lumbar SC extracts confirmed the ability of 2a to increase VPS35 and VPS26b levels in G93A mice (Supplementary Fig. 11a, b).”
Quote in the paperSubstantial claim - Findingown data
Vehicle-treated G93A mice display abundant poly-ubiquitinated proteins.
“Vehicle-treated G93A mice displayed abundant poly-ubiquitinated proteins whereas their levels were substantially reduced by compound 2a (Fig. 7b).”
Quote in the paperSubstantial claim - Findingown data
Treatment with compound 2a significantly increases VPS35 mean fluorescence intensity levels in motor neurons of G93A mice.
“In contrast, treatment with compound 2a significantly increased such levels in MNs of G93A mice (Fig. 6a).”
Quote in the paperSubstantial claim - Findingown data
VPS35 is reduced in motor neurons from ALS post mortem explants.
“We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice.”
Quote in the paperSubstantial claim - Findingown data
There is a substantial reduction of CRC proteins in motor neurons of G93A mice.
“We describe a substantial reduction of CRC proteins in MNs of G93A mice.”
Quote in the paperSubstantial claim - Findingown data
G93A mice receiving compound 2a-driven retromer stabilization show a substantial reduction of high molecular weight SOD1 aggregates.
“Similarly, G93A mice receiving compound 2a-driven retromer stabilization showed a substantial reduction of high molecular weight SOD1 aggregates.”
Quote in the paperSubstantial claim - Findingown data
The pathological phenomenon of poly-ubiquitinated protein accumulation is significantly reduced in vitro and in vivo by compound 2a.
“Such pathological phenomenon was significantly reduced in vitro and in vivo by compound 2a.”
Quote in the paperSubstantial claim - Interpretationown data
Compound 2a is selected as an early lead.
“Therefore, phenyl-1,3-bis-guanylhydrazone 2a was selected as an early lead.”
Quote in the paperSubstantial claim - Interpretationreasoning
The retromer could be an early therapeutic target in ALS.
“This alteration occurs early in G93A mice, suggesting that the retromer could be an early therapeutic target in ALS, albeit future investigations are needed to identify mechanisms leading to retromer failure in ALS MNs.”
Quote in the paperNot a substantial claim - Interpretationown data
Compound 2a can be used to stabilize the retromer complex in ALS models.
“Altogether, these results suggest that compound 2a can be used to stabilize the retromer complex in ALS models.”
Quote in the paperSubstantial claim - Premisecitation
Golgi fragmentation is commonly observed in motor neurons of sALS and fALS patients.
“Golgi fragmentation is commonly observed in MNs of sALS and fALS patients35,68.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] Mourelatos, Z. et al. Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis revealed by organelle-specific antibodies. Proc. Natl Acad. Sci. USA 87, 4393–4395 (1990). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [68] Gonatas, N. K. et al. Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis. Am. J. Pathol. 140, 731–737 (1992).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Compound 2a has a wide therapeutic window.
“These results indicate a wide therapeutic window for compound 2a, considering the low μM concentration needed in vitro to increase VPS35 levels.”
Quote in the paperSubstantial claim - Premisereasoning
The pKa range of guanylhydrazones should ensure higher permeability through lipophilic bio-membranes.
“The pKa range of guanylhydrazones should ensure a higher permeability through lipophilic bio-membranes, due to an estimated ≈16% free base at 37 °C and pH = 7.428.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Diamant, S., Agranat, I., Goldblum, A., Cohen, S. & Atlas, D. Beta-adrenergic activity and conformation of the antihypertensive specific alpha 2-agonist drug, guanabenz. Biochem. Pharm. 34, 491–498 (1985). source
- Interpretationown data
The reduction of VPS35 protein in G93A mice is not caused by transcriptional inhibition.
“Despite the reduction of VPS protein levels, their mRNA levels did not drop significantly when compared with WT controls, suggesting that their reduction was not caused by transcriptional inhibition (Fig. 1f).”
Quote in the paperNot a substantial claim - Interpretationown data
The retromer is a valuable druggable target in ALS.
“Our results clearly suggest the retromer as a valuable druggable target in ALS.”
Quote in the paperSubstantial claim - Premisecitation
The ALS-linked G93A mutation of SOD1 allowed the establishment of a mouse model featuring MN degeneration in the spinal cord.
“The ALS-linked G93A mutation of SOD1 allowed the establishment of a mouse model, featuring MN degeneration in the SC4.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Bruijn, L. I., Miller, T. M. & Cleveland, D. W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749 (2004). source
- Premisecitation
Loss of any CRC component leads to instability and rapid degradation of the remaining proteins.
“These results confirm that a loss of any of the CRC components leads to instability and rapid degradation of the remaining proteins25.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Seaman, M. N. J. Retromer and its role in regulating signaling at endosomes. Prog. Mol. Subcell. Biol. 57, 137–149 (2018). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
Pharmacological retromer stabilizers could be useful to delay degenerative processes occurring in ALS.
“Therefore, pharmacological retromer stabilizers could be useful to delay degenerative processes occurring in ALS.”
Quote in the paperSubstantial claim - Interpretationcitation
Lysosomal alterations probably concur to increase the accumulation of poly-ubiquitinated proteins in the lumbar spinal cord.
“Lysosomal alterations probably concur to increase the accumulation of poly-ubiquitinated proteins in the lumbar SC72.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [72] Stieber, A., Gonatas, J. O. & Gonatas, N. K. Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuronal and astrocytic perikarya of mice expressing the SOD1(G93A) mutation of familial amyotrophic lateral sclerosis. J. Neurol. Sci. 177, 114–123 (2000). source
- Interpretationown data
The functional effects of compound 2a correlate with its ability to increase CRC protein levels in motor neurons.
“These functional effects correlate with the ability of 2a to increase CRC protein levels in MNs, but further experiments with VPS35 conditional KO mice will further validate in vivo the mechanism of action of compound 2a.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 31
- Probably not a substantial claim. 25
- The quote only partly states this claim. 2
It may state two separate claims as one.
PremisecitationOverexpression of mutant SOD1 increases rates of cell death in MN-like NSC-34 cells, and SOD1G93A affects Neuro2a cell survival.
“The overexpression of mutant SOD1 increases rates of cell death in MN-like NSC-34 cells5, and SOD1G93A affects Neuro2a cell survival63.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Grad, L. I. et al. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc. Natl Acad. Sci. USA 111, 3620–3625 (2014). source
- cites [63] Oh, Y. K., Shin, K. S., Yuan, J. & Kang, S. J. Superoxide dismutase 1 mutants related to amyotrophic lateral sclerosis induce endoplasmic stress in neuro2a cells. J. Neurochem. 104, 993–1005 (2008). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe CRC core element of the retromer and the SNX dimer assemble to create a functional retromer complex.
“The CRC core element of the retromer and the SNX dimer assemble to create a functional retromer complex8,22,61.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [8] Seaman, M. N. Recycle your receptors with retromer. Trends Cell Biol. 15, 68–75 (2005). source
- cites [22] Seaman, M. N. The retromer complex—endosomal protein recycling and beyond. J. Cell Sci. 125, 4693–4702 (2012). source
- cites [61] Cullen, P. J. & Korswagen, H. C. Sorting nexins provide diversity for retromer-dependent trafficking events. Nat. Cell Biol. 14, 29–37 (2011). source
It may state two separate claims as one.
PremisecitationThe Golgi apparatus is affected in MNs from ALS patients and in cells overexpressing mutant SOD1 forms.
“The Golgi apparatus is affected in MNs from ALS patients and in cells overexpressing mutant SOD1 forms35–37.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [35] Mourelatos, Z. et al. Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis revealed by organelle-specific antibodies. Proc. Natl Acad. Sci. USA 87, 4393–4395 (1990). source
The Abstract in our copy reports fragmentation of the Golgi apparatus in motor neurons in amyotrophic lateral sclerosis, supporting the claim about patients. It does not address cells overexpressing mutant SOD1, so it does not support that part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [36] Urushitani, M., Ezzi, S. A., Matsuo, A., Tooyama, I. & Julien, J. P. The endoplasmic reticulum-Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS. FASEB J. 22, 2476–2487 (2008). source
- cites [37] Fujita, Y. et al. Fragmentation of the Golgi apparatus of Betz cells in patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 163, 81–85 (1999). source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationA mutant form of VAP-B (P56S) was described in a family of ALS patients, and VAP-B levels are dampened in motor neurons of G93A mice.
“A mutant form of VAP-B (P56S) was described in a family of ALS patients69, and VAP-B levels are dampened in MNs of G93A mice70.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [69] Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75, 822–831 (2004). source
- cites [70] Teuling, E. et al. Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. J. Neurosci. 27, 9801–9815 (2007). source
It may state two separate claims as one.
PremisecitationThe retromer complex interacts with VAP-B, and this interaction occurs in regions where the ER makes contacts with endosomes.
“The retromer complex interacts with VAP-B and such interaction occurs in regions in which the ER makes contacts with endosomes71.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [71] Dong, R. et al. Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166, 408–423 (2016). source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe retromer recycles specific cargos including CI-MPR, which is involved in delivery of proteolytic enzymes to lysosomes.
“The retromer recycles specific cargos, such as Vps10/Sortilin protein family members14 or the cation-independent mannose 6-phosphate receptor (CI-MPR)15. The latter is involved in the delivery of proteolytic enzymes to lysosomes.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [14] Seaman, M. N., Marcusson, E. G., Cereghino, J. L. & Emr, S. D. Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. J. Cell Biol. 137, 79–92 (1997). source
- cites [15] Arighi, C. N., Hartnell, L. M., Aguilar, R. C., Haft, C. R. & Bonifacino, J. S. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J. Cell Biol. 165, 123–133 (2004). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA point mutation in VPS35 (D620N) is causative of an autosomal dominant form of Parkinson's disease.
“A point mutation in VPS35 (D620N) is causative of an autosomal dominant form of Parkinson’s disease (PD)16,17”
Quote in the paperNot a substantial claim2 of 2 sources checkedIt may state two separate claims as one.
PremisecitationLysosomal deficits are well documented in G93A mice, and starting from day 40, CTSD levels are significantly reduced in motor neurons from these mice.
“Lysosomal deficits are well documented in G93A mice and starting from day 40, the levels of CTSD are significantly reduced in MNs7 from these mice.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Xie, Y. et al. Endolysosomal deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS mice. Neuron 87, 355–370 (2015). source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationStrengthening the interaction between proteins assembled in the CRC bolsters full retromer stability and increases its functionality.
“On the other hand, strengthening the interaction between proteins assembled in the CRC bolsters full retromer stability, and increases its functionality as elegantly described20.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014). source
It may state two separate claims as one.
Interpretationown dataLoss of retromer functionality alters lysosomal homeostasis and the accumulation of poly-ubiquitinated proteins.
“We next assessed that poly-ubiquitinated protein levels were doubled in Neuro2a cells receiving a VPS35-targeted RNAi, suggesting that loss of retromer functionality alters lysosomal homeostasis and the accumulation of poly-ubiquitinated proteins (Supplementary Fig. 12d, e)21.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Seaman, M. N. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004). source
The Results section (page unavailable) reports that mVPS26 knockdown severely impaired maturation of the lysosomal enzyme cathepsin D, supporting an effect on lysosomal function. It does not report accumulation of poly-ubiquitinated proteins. The doubled levels in Neuro2a cells are presented as the citing authors’ own result, not a finding of this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationPharmacological tools increasing interaction between CRC members increase retromer stability and enhance retromer-mediated trafficking of cargos.
“Pharmacological tools, increasing the interaction between members of the CRC complex, increase retromer stability and enhance retromer-mediated trafficking of cargos.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014). source
It may state two separate claims as one.
PremisecitationThe maturation of CTSD involves CI-MPR and a functional retromer.
“The maturation of this lysosomal enzyme involves CI-MPR and a functional retromer21.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Seaman, M. N. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004). source
It may state two separate claims as one.
PremisecitationMutant SOD1 proteins misfold, filling MNs with toxic aggregates, which impinge on their survival.
“Mutant SOD1 proteins misfold, filling MNs with toxic aggregates, which impinge on their survival5.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Grad, L. I. et al. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc. Natl Acad. Sci. USA 111, 3620–3625 (2014). source
In “Cellular Import and Export of the SOD1 Transmission Particle” (page unavailable), the paper reports SOD1 aggregates and significant cell death in transfected motor neuron-like cells, supporting the link between misfolded SOD1 and impaired cell survival. It does not show that aggregates fill actual motor neurons or establish that those aggregates cause their death. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductcitationThe numbers of mice were determined by preliminary results or literature precedent.
“We determined numbers of mice by preliminary results or literature precedent76.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [76] Rossi, C. et al. Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis. Cell Death Dis. 9, 250 (2018). source
It may state two separate claims as one.
Findingown dataVPS35 levels are reduced in motor neurons of postmortem ALS patients and in human iPSC-derived motor neurons from fALS patients.
“Similarly, we observe a reduction of VPS35 levels in MNs scored in postmortem ALS patients, and in human iPSC-derived MNs from fALS patients.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCTSD levels and CTSD+ puncta are significantly reduced in motor neurons of vehicle-treated G93A mice.
“We next analyzed CTSD levels and CTSD+ puncta in MNs by confocal microscopy, observing their significant reduction in MNs of vehicle-treated G93A mice that was restored by treatment with compound 2a (Fig. 6f).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBoth control and ALS 27 cells significantly increase VPS35+ puncta when treated with compound 2a.
“ALS 27 cells displayed less VPS35+ puncta than controls, albeit both cell types significantly increased VPS35+ puncta when treated with compound 2a (Fig. 8g).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTransgenic G93A mice and their WT litters well tolerated intraperitoneally delivered compound 2a, with no observed distress, aberrant behavior or pain.
“Transgenic mice and their WT litters well tolerated intraperitoneally delivered compound 2a, as we did not observe distress, aberrant behavior or pain in treated mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingnone givenCompound 2a displays the lowest Kd value among molecules 2a-6a.
“Compound 2a displays the lowest Kd value among molecules 2a–6a”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
Findingnone givenSuch retromer stabilizers possess good in vivo bioavailability, potency, and stability.
“Such retromer stabilizers possess good in vivo bioavailability, potency, and stability.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataThe rates of ISLET1+ cell differentiation are similar among control and ALS cells.
“We scored the ISLET1+ percentage among nuclei, observing similar rates of cell differentiation among controls and ALS cells (controls: 81.6% ± 9; ALS: 81.8% ± 12, Supplementary Fig. 15d, e).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataCompound 2a significantly counteracts cell death and reduces LDH release in Neuro2a cells transfected with SOD1G93A plasmids.
“Compound 2a significantly counteracted cell death and reduced LDH release in Neuro2a cells transfected with SOD1G93A plasmids.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCompound 2a is a potent and bioavailable interactor of VPS35-VPS29.
“We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn compound 2a-treated G93A mice, neither CD14 levels nor the total number of Iba1+ cells changed compared with vehicle-treated G93A mice.
“Neither CD14 levels nor the total number of Iba1+ cells changed in compound 2a-treated G93A mice when compared with vehicle-treated mice (Supplementary Fig. 10a–c).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataCompound 2a increases VPS35 protein levels in ALS iPSC-derived motor neurons.
“We next used WB for o confirm the ability of compound 2a to increase VPS35 protein levels in ALS cells (Fig. 8h).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataHigh molecular weight SOD1 smears are present in spinal cord extracts of G93A mice and absent in WT litters.
“we observed high molecular weight smears in G93A mice that were absent in WT litters.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataCompound 2a causes a slight, but not significant, reduction of body weight in WT and G93A mice.
“We observed a slight, but not significant reduction of body weight in both WT and G93A mice (Fig. 4a).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataCompound 2a treatment increases levels of both CI-MPR and CTSD in motor neurons of G93A mice.
“We observed increased levels of both CI-MPR and CTSD in MNs of G93A mice treated with compound 2a.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCompound 2a fails to rescue Neuro2a cell survival and to inhibit LDH release in the presence of VPS35-targeted siRNA.
“we observed that it failed to rescue Neuro2a cell survival and to inhibit LDH release in presence of VPS35-targeted siRNA.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCompound 2a treatment restores CTSD levels and CTSD+ puncta in motor neurons of G93A mice.
“We next analyzed CTSD levels and CTSD+ puncta in MNs by confocal microscopy, observing their significant reduction in MNs of vehicle-treated G93A mice that was restored by treatment with compound 2a (Fig. 6f).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCompound 2a attenuates locomotion impairment in G93A mice and significantly increases the number of surviving motor neurons.
“Compound 2a attenuated locomotion impairment in G93A mice, and significantly increased the number of surviving MNs.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataEither VPS35 knockdown or overexpression of SOD1G93A in Neuro2a cells increases poly-ubiquitinated protein levels.
“we observed that either VPS35 knockdown or overexpression of SOD1G93A in Neuro2a cells increased poly-ubiquitinated protein levels.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationPhenyl and thiophene rings are bio-isosters.
“Phenyl and thiophene rings are bio-isosters26”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Convertino, M., Das, J. & Dokholyan, N. V. Pharmacological chaperones: design and development of new therapeutic strategies for the treatment of conformational diseases. ACS Chem. Biol. 11, 1471–1489 (2016). source
It may state two separate claims as one.
PremisecitationTreatment of neurons carrying pathogenic APP mutations with R55/1 reduces the accumulation of amyloid-β peptides and APP processing.
“Treatment of neurons carrying pathogenic APP mutations with R55/1 reduced the accumulation of amyloid-β (Aβ) peptides as well as APP processing20.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014). source
It may state two separate claims as one.
PremisecitationGuanylhydrazones show good stability and a pKa range closer to neutrality due to delocalization of their charge on three N atoms.
“We substituted isothioureas with guanylhydrazones, as the latter groups show good stability and a pKa range closer to neutrality due to the delocalization of their charge on three N atoms (favored azine form vs. disfavored hydrazone form, 4.5 ≤ ΔGT ≤ 6.5 Kcal/mol27, Supplementary Fig. 3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chourasiya, S. S. et al. Azine-hydrazone tautomerism of guanylhydrazones: evidence for the preference toward the azine tautomer. J. Org. Chem. 81, 7574–7583 (2016). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataALS iPSC lines have a normal karyotype.
“We observed a normal karyotype in ALS cell lines (Supplementary Fig. 15a).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationR55/1 stabilizes the VPS35-VPS29 interaction, increases retromer levels in vitro, and decreases pathogenic processing of APP in cells.
“The isothiourea chaperone R55/1 stabilizes the VPS35-VPS29 interaction, increases retromer levels in vitro, and decreases pathogenic processing of APP in cells20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014). source
Probably not a substantial claim.
PremisecitationDelivery of proteolytic enzymes to lysosomes needs coordinated action of multiple protein regulators, among which the highly conserved retromer complex.
“Delivery of proteolytic enzymes to lysosomes needs the coordinated action of multiple protein regulators, among which the highly conserved retromer complex8.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Seaman, M. N. Recycle your receptors with retromer. Trends Cell Biol. 15, 68–75 (2005). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationNeurons degrade aggregated proteins only through the ubiquitin-proteasome system or the autophagy-lysosomal pathway.
“neurons degrade these aggregates only through the ubiquitin-proteasome system, or the autophagy-lysosomal pathway6.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780–786 (2006). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationVPS35 deficiency alters distribution of Lamp2a in neurons.
“VPS35 deficiency alters the distribution of lysosome-associated membrane glycoprotein 2a (Lamp2a) in neurons19.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Tang, F. L. et al. VPS35 in dopamine neurons is required for ēndosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for alpha-synuclein degradation and prevention of pathogenesis of Parkinson’s disease. J. Neurosci. 35, 10613–10628 (2015). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationKnockdown of a single CRC protein affects the expression of the other CRC members.
“Knockdown of a single CRC protein affects the expression of the other CRC members15,21.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Arighi, C. N., Hartnell, L. M., Aguilar, R. C., Haft, C. R. & Bonifacino, J. S. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J. Cell Biol. 165, 123–133 (2004). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [21] Seaman, M. N. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004). source
It may state two separate claims as one.
Interpretationown dataCompound 2a counteracts SOD1G93A-mediated cytotoxicity by increasing VPS35 levels and retromer functionality.
“Notably, incubation of SOD1G93A-Sh56 double transfected cells with compound 2a modestly increased cell viability, confirming that compound 2a counteracts SOD1G93A-mediated cytotoxicity by increasing VPS35 levels and retromer functionality.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationBis-isothiourea R55/1 increases VPS35 levels (∼60%) in cells and the general stability of the retromer complex.
“Among them, bis-isothiourea R55/1 increased VPS35 levels (∼60%) in cells, and therefore the general stability of the retromer complex20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014). source
It may state two separate claims as one.
Interpretationown dataRetromer stabilization mediated by compound 2a increases lysosomal homeostasis in vitro and in vivo, decreases protein polyubiquitination and diminishes G93A aggregation.
“These results suggest that retromer stabilization mediated by compound 2a increases lysosomal homeostasis in vitro and in vivo, decreases protein polyubiquitination and diminishes G93A aggregation.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenIn each Golgi morphology experiment, cells were randomly sampled across three coverslips.
“In each experiment, cells were randomly sampled across three coverslips.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataSciatic nerve specimens were blindly examined by light microscopy using a ×40 objective.
“We stained sections with toluidine blue and specimens were blindly examined by light microscopy using ×40 objective.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAn operator blind to disease status and demographic data evaluated the immunohistochemistry sections.
“An operator that was blind to the disease status and demographic data subsequently evaluated these sections.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenMaximum LDH release control was obtained by lysing untreated Neuro2a cells with 2 μL of 10% Triton X-100.
“Maximum LDH Release Control was obtained lysing untreated Neuro2a cells with 2 μL of 10% Triton X-100 (Sigma–Aldrich).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataIn LDH cytotoxicity experiments, parallel positive controls treating cells with 200 μM H2O2 were run.
“we run parallel positive controls treating cells with 200 µM H2O2.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAn operator blind to treatment performed injections and manipulation of mice.
“An operator blind to the treatment performed injections and manipulation of mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenKaryotyping analysis of the human iPS cell lines was performed by ISENET Biobanking service unit in Milan, Italy.
“The karyotyping analysis was performed by ISENET Biobanking service unit in Milan, Italy (www.isenetbiobanking.com).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductnone givenAll experiments in this study were carried out at least in triplicate.
“All experiments were carried out at least in triplicate.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenData normality was assessed using either the Kolmogorov-Smirnov test (with Dallas-Wilkinson-Lille for P-value) or the D'Agostino & Pearson omnibus normality test.
“We assessed normality of data applying either Kolmogorov–Smirnov test (with Dallas–Wilkinson–Lille for P-value) or D'Agostino & Pearson omnibus normality test.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The SOD1G93A mouse model and human ALS samples are representative of ALS pathophysiology.
“We used compound 2a to restore retromer levels in G93A mice.”
The paper relies on this without support.
The antibodies and immunofluorescence quantifications specifically detect the intended proteins.
“labelled for: VPS35/NeuN (a), VPS26/NeuN (b), CI-MPR/NeuN (c), Sortilin/NeuN (d), and CTSD/NeuN (f).”
The paper relies on this without support.
The observed reduction in retromer proteins in ALS motor neurons is not an artifact of postmortem tissue or cell culture.
“VPS35 immunoreactivity was substantially reduced in ALS MNs, confirming our observations in G93A mice (Fig. 8b).”
The paper relies on this without support.
The iPSC-derived motor neurons from ALS patients recapitulate ALS disease processes.
“We next generated iPSC lines from fibroblasts obtained from fALS patients carrying three SOD1 gene variants (ALS 8: p.Asn65Ser; ALS 13: p.Leu144Phe; ALS 27: p.Asp97Asn), and from three healthy volunteers.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The endosomal network is a key biological pathway affected in neurodegenerative pathology.
“These studies, alongside clinical evidence [8][9][10][11][12][13][14], highlight the endosomal network as a key biological pathway affected in neurodegenerative pathology.”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [11]
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.
VPS26 increase is called significant despite p = 0.09
MajorThe results state that compound 2a significantly increased VPS26 fluorescence in G93A mice, but the figure caption reports p = 0.09 for that comparison. The paper defines statistical significance as p < 0.05.
“As expected, MFI levels were reduced in vehicle-treated G93A mice, while they were significantly increased in compound 2a-treated mice (Fig. 6b).”
“G93A-v vs. G93A-2a p = 0.09, other comparisons p < 0.0001”
Compound 3a is assigned conflicting chemical groups
MinorThe results identify compound 3a as a guanylhydrazone, whereas the Fig. 2 caption calls it a bis-isothiourea.
“We then replaced isothioureas with two meta-guanylhydrazones (compound 3a, violet in Fig. 2e)”
“e docking poses of 1,3-phenyl bis-isothiourea 3a (violet carbon atoms)”
Fig. 1 gives conflicting ages for the VPS35 western blots
MinorThe Fig. 1 caption says the VPS35 western blots include mice at day 100, but gives the corresponding third comparison as day 90.
“c WBs for VPS35 and β-Actin in lumbar SCs protein extracts from WT and G93A mice at 20, 60, and 100 days”
“WT vs. G93A day20: p = 0.007; day 60: p = 0.0015; day 90: p < 0.0001”
Compound 5a is described as both meta- and para-substituted
MinorThe results describe compound 5a as para-substituted, while the Fig. 2 caption calls its 1,4 substitution meta.
“Para substitution showed a reduced interaction (calculated Kd = 290.6 µM) with low recurrence (normalized Kd = 561 µM-7/40 poses) through repositioning of an isothiourea group in 5a”
“1,4-meta substituted 5a (cyan carbon atoms) repositions an isothiourea group in surface recess 2”
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1038/s41380-019-0364-x
InfoThe cited work was retracted on 2022-10-18 (notice 10.1038/s41380-022-01814-1), not before this paper was published (2020-07-31).
Cited work 10.1038/s41380-019-0364-x · retracted 2022-10-18 · notice 10.1038/s41380-022-01814-1 · this paper published 2020-07-31
“Li, J. G., Chiu, J. & Pratico, D. Full recovery of the Alzheimer’s disease phenotype by gain of function of vacuolar protein sorting 35. Mol. Psychiatry https://doi.org/10.1038/s41380-019-0364-x (2019).”
Citations
Cites
1 retracted
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RetractedAutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21256 · Cited by 26,294
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Self-citation
Metadata
- Authors
- Muzio, L., Sirtori, R., Gornati, D., Eleuteri, S., Fossaghi, A., Brancaccio, D., Manzoni, L., Ottoboni, L., Feo, L. D., Quattrini, A., Mastrangelo, E., Sorrentino, L., Scalone, E., Comi, G., Marinelli, L., Riva, N., Milani, M., Seneci, P., & Martino, G.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- University of Milan (IT)
- University of Naples Federico II (IT)
- Institute of Molecular Science and Technologies (IT)
- National Research Council (IT)
- Corresponding author
- Muzio, Luca
- ORCID
- Venue
- Nature Communications
- Published
- 2020-07-31
- Volume
- 11
- Issue
- 1
- Pages
- 3848-3848
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7395176
- OpenAlex
- W3046886447
- Cited by
- 65
- References
- 83
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 11 · 2021: 15 · 2020: 3
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Target ALS
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- amyotrophic lateral sclerosis, retromer complex, VPS35, VPS29, motor neuron survival, neuroprotection, SOD1 G93A mice, iPSC-derived motor neurons, drug discovery, locomotor impairment
- MeSH terms
- Neuroprotection, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Brain, Cell Differentiation, Cell Survival, Disease Models, Animal, Humans, Hydrazones, Locomotion, Male, Mice, Transgenic, Motor Neurons, Protein Binding, Structure-Activity Relationship, Neuroprotective Agents, Vesicular Transport Proteins, Mice, Protein Multimerization, Induced Pluripotent Stem Cells
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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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