The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index; 1 of the 35 sources its claims cite were checked for support.
Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice
Open accessAbstract
Huntington's disease (HD) disturbs glucose metabolism in the brain by poorly understood mechanisms. HD neurons have defective glucose uptake, which is attenuated upon enhancing rab11 activity. Rab11 regulates numerous receptors and transporters trafficking onto cell surfaces; its diminished activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1. Glucose transporter 3 (Glut3) handles most glucose uptake in neurons. Here we investigated rab11 involvement in Glut3 trafficking. Glut3 was localized to rab11 positive puncta in primary neurons and immortalized striatal cells by immunofluorescence labeling and detected in rab11-enriched endosomes immuno-isolated from mouse brain by Western blot. Expression of dominant active and negative rab11 mutants in clonal striatal cells altered the levels of cell surface Glut3 suggesting a regulation by rab11. About 4% of total Glut3 occurred at the cell surface of primary WT neurons. HD(140Q/140Q) neurons had significantly less cell surface Glut3 than did WT neurons. Western blot analysis revealed comparable levels of Glut3 in the striatum and cortex of WT and HD(140Q/140Q) mice. However, brain slices immunolabeled with an antibody recognizing an extracellular epitope to Glut3 showed reduced surface expression of Glut3 in the striatum and cortex of HD(140Q/140Q) mice compared to that of WT mice. Surface labeling of GABAα1 receptor, which is not dependent on rab11, was not different between WT and HD(140Q/140Q) mouse brain slices. These data define Glut3 to be a rab11-dependent trafficking cargo and suggest that impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Glut3 is a rab11-dependent trafficking cargo, and its transport to the neuronal cell surface is reduced in HD140Q/140Q neurons and adult HD mouse brain despite normal total Glut3 levels. The findings suggest that impaired rab11-dependent Glut3 trafficking contributes to glucose hypometabolism in Huntington’s disease.
Key findings
- In primary cortical neurons, Glut3 co-localized with rab11: 35.3 ± 10.7% of Glut3 puncta contained rab11, and 44.4 ± 9.5% of rab11 puncta were Glut3-positive (n = 20 neurite segments from 20 neurons).
- About 4.37 ± 2.58% of endogenous Glut3 was on the cell surface in WT primary neurons; biotinylated Glut3 in HD140Q/140Q neurons was reduced by 31.8 ± 14.62% relative to WT (n = 3 experiments, p < 0.05).
- In STHdhQ7/Q7 striatal cells, dominant active rab11 increased and dominant negative rab11 decreased cell surface Glut3 without changing total Glut3; STHdhQ111/Q111 cells had impaired glucose uptake and about 4.5-fold higher total Glut3 than WT cells.
- In 9–10-month-old HD140Q/140Q mouse brain, total Glut3 was comparable to WT in cortex and striatum, but surface Glut3 was reduced by about 11% in cortex and 15% in striatum; surface GABAα1, a non-rab11-dependent cargo, was not different.
Methods
- Primary cortical neurons from E16–E18 WT and HD140Q/140Q mice, immortalized STHdhQ7/Q7 and STHdhQ111/Q111 striatal cells, and adult WT and HD140Q/140Q mouse brain tissue were used.
- Cell surface proteins were analyzed by biotinylation, immunofluorescence, subcellular fractionation, rab11 immuno-isolation, SDS-PAGE/Western blot, and non-permeabilized brain slice immunohistochemistry.
- Quantification used NIH ImageJ densitometry and signal intensity/cross-sectional area measurements, with two-tailed Student t-tests for statistical comparisons.
Limitations
- The paper does not include a formal limitations section. It states that biotinylated Glut3 signals were extremely low and hardly detected in some experiments, and that technical difficulties in enriching cell surface Glut3 from primary neurons led to using immortalized striatal cells.
- Evident from the text: some analyses rely on small samples, including n = 3 experiments for primary neuron biotinylation, 6 WT and 6 HD mice for Western blots, and 2 WT and 2 HD mice for some brain slice quantifications.
- Evident from the text: the in vivo evidence is correlational, and although GABAα1 was used to address neuronal shrinkage, the surface Glut3 reductions are modest and the study does not directly manipulate rab11 activity in adult HD brain.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
1 of 35 cited sources checked · 1 supported · 0 flagged
- Premisecitation
Glut3 handles most glucose uptake in neurons.
“Glucose transporter 3 (Glut3) handles most glucose uptake in neurons.”
- Also stated in: § Defective trafficking of Glut3 to cell surfaces in primary HD neurons · hedged
“Glut3 is believed to mediate the majority of glucose uptake in neurons.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [10] Duelli R, Kuschinsky W: Brain glucose transporters: relationship to local energy demand. News Physiol Sci 2001, 16: 71–76. source
- cites [11] McEwen BS, Reagan LP: Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 2004, 490(1–3):13–24. 10.1016/j.ejphar.2004.02.041 source
- cites [12] Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ: The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 2008, 295(2):E242-E253. 10.1152/ajpendo.90388.2008 source
- Also stated in: § Defective trafficking of Glut3 to cell surfaces in primary HD neurons · hedged
- Findingown data
Glut3 is present in rab11-enriched endosomes immuno-isolated from mouse brain.
“Glut3 was detected in immuno-enriched organelles using anti-rab11 antibody but not in immuno-enriched organelles isolated using anti-FLAG antibody (control antibody) (Figure 2C).”
- Also stated in: § Abstract · plain
“Glut3 was localized to rab11 positive puncta in primary neurons and immortalized striatal cells by immunofluorescence labeling and detected in rab11-enriched endosomes immuno-isolated from mouse brain by Western blot.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Western blot analysis reveals comparable levels of Glut3 in the striatum and cortex of WT and HD140Q/140Q mice.
“Western blot analysis revealed comparable levels of Glut3 in the striatum and cortex of WT and HD140Q/140Q mice.”
Quote in the paperSubstantial claim - Findingown data
Surface labeling of GABAα1 receptor is not different between WT and HD140Q/140Q mouse brain slices.
“Surface labeling of GABAα1 receptor, which is not dependent on rab11, was not different between WT and HD140Q/140Q mouse brain slices.”
Quote in the paperSubstantial claim - Findingown data
Viral expression of either dNrab11 or dArab11 does not affect overall levels of Glut3 protein in STHdhQ7/Q7 cells.
“Viral expression of either dNrab11 or dArab11 did not affect overall levels of Glut3 protein in STHdhQ7/Q7 cells (Figure 3D).”
Quote in the paperSubstantial claim
- Findingown data
About 4% of Glut3 is located on the cell surface in primary cortical neurons.
“In this study we found that about 4% of Glut3 is located on the cell surface in primary cortical neurons.”
Quote in the paperSubstantial claim - Findingown data
HD140Q/140Q mice at 9-10 months of age express levels of Glut3 protein comparable to WT in the cortex and the striatum.
“The data in Figure 4 showed that HD140Q/140Q mice at 9–10 months of age expressed levels of Glut3 protein comparable to WT in the cortex and the striatum”
Quote in the paperSubstantial claim - Findingown data
Brain slices immunolabeled with an antibody recognizing an extracellular epitope to Glut3 show reduced surface expression of Glut3 in the striatum and cortex of HD140Q/140Q mice compared to WT mice.
“However, brain slices immunolabeled with an antibody recognizing an extracellular epitope to Glut3 showed reduced surface expression of Glut3 in the striatum and cortex of HD140Q/140Q mice compared to that of WT mice.”
Quote in the paperSubstantial claim - Findingown data
Glut3 expression on neuronal cell surfaces is reduced in brain regions that are most affected in HD.
“We found that Glut3 expression on neuronal cell surfaces was reduced in brain regions that are most affected in HD.”
Quote in the paperSubstantial claim - Findingown data
Total Glut3 protein levels in STHdhQ111/Q111 cells are about 4.5-fold higher than in WT STHdhQ7/Q7 cells.
“Like primary HD140Q/140Q neurons [25], STHdhQ111/Q111 cells were impaired in taking up glucose although total levels of Glut3 protein in STHdhQ111/Q111 cells were about 4.5-fold higher than those in WT STHdhQ7/Q7 cells (Figure 3A and B).”
Quote in the paperSubstantial claim - Findingown data
About 4% of total Glut3 is located at the cell surface of primary WT neurons.
“Densitometrical analysis revealed that 4.37 ± 2.58% of endogenous Glut3 was located on the cell surface (n = 3 experiments) in WT neurons.”
- Also stated in: § Abstract · plain
“About 4% of total Glut3 occurred at the cell surface of primary WT neurons.”
Quote in the paperNot a substantial claim - Also stated in: § Abstract · plain
- Findingown data
The immuno-reactive signals for GABAα1 at the cell surface are comparable in WT and HD brain slices.
“However, the immuno-reactive signals for GABAα1 at the cell surface were comparable in WT and HD brain slices”
Quote in the paperSubstantial claim - Findingown data
Primary HD140Q/140Q cortical neurons are impaired in taking up glucose.
“In agreement with this idea, primary HD140Q/140Q cortical neurons were impaired in taking up glucose, the first step for neurons to utilize glucose.”
Quote in the paperSubstantial claim - Findingown data
HD140Q/140Q neurons express normal levels of Glut3 protein.
“Relative to WT neurons, HD140Q/140Q neurons expressed normal levels of Glut3 protein, but displayed less Glut3 on the cell surface, suggesting that there is a deficit of Glut3 trafficking to the cell surface in HD neurons.”
Quote in the paperSubstantial claim - Findingown data
STHdhQ111/Q111 cells are impaired in taking up glucose.
“Like primary HD140Q/140Q neurons [25], STHdhQ111/Q111 cells were impaired in taking up glucose although total levels of Glut3 protein in STHdhQ111/Q111 cells were about 4.5-fold higher than those in WT STHdhQ7/Q7 cells (Figure 3A and B).”
Quote in the paperSubstantial claim - Findingown data
HD140Q/140Q primary neurons have significantly less cell surface Glut3 than WT neurons.
“Densitometrical analysis of results from three experiments with detectable biotinylated Glut3 signals in both WT and HD140Q/140Q neurons showed that signals for biotinylated Glut3 in HD neurons were reduced by 31.8 ± 14.62% relative to biotinylated Glut3 signals in WT neurons (n = 3 experiments, Mean ± SD, two-tailed Student t-test: p < 0.05; Figure 1B).”
- Also stated in: § Abstract · plain
“HD140Q/140Q neurons had significantly less cell surface Glut3 than did WT neurons.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In STHdhQ7/Q7 cells, structures containing both Glut3 and rab11 are present.
“Arrows in enlarged photos indicate structures containing both Glut3 and rab11.”
Quote in the paperSubstantial claim - Findingown data
Glucose uptake is defective in immortalized STHdhQ111/Q111 striatal cells.
“Defective glucose uptake in immortalized STHdhQ111/Q111 striatal cells.”
Quote in the paperSubstantial claim - Findingown data
The cross-sectional area of HD cortical and striatal neurons is significantly decreased by about 15% compared to WT neurons.
“There was also a significant decrease (about 15%) in the cross-sectional area of the HD cortical and striatal neurons compared to those of WT neurons”
Quote in the paperNot a substantial claim - Findingown data
Glut3 immuno-reactive signals are significantly reduced by about 11% in the cortex and 15% in the striatum of HD140Q/140Q brain slices relative to WT brain slices.
“We found that Glut3 immuno-reactive signals were significantly reduced by about 11% in cortex and 15% in striatum of HD140Q/140Q brain slices relative to those in WT brain slices”
Quote in the paperSubstantial claim - Findingown data
The cross-sectional area of GABAα1 positive cortical neurons is significantly reduced by 27% in HD brain slices.
“The cross sectional area of GABAα1 positive cortical neurons was significantly reduced by 27% in HD brain slices”
Quote in the paperNot a substantial claim - Findingown data
In the cortex of WT and HD mice, there is no difference in overall levels of GABAα1 protein.
“In the cortex of WT and HD mice, no difference in overall levels of GABAα1 protein was revealed by Western blot assay (N = 6 WT and 6 HD cortex samples compared, data not shown).”
Quote in the paperSubstantial claim - Findingown data
The defect of Glut3 trafficking is also present in the brain of adult HD140Q/140Q mice.
“Using an antibody-binding assay to detect protein expression on neuronal cell surfaces in non-permeabilized brain slices of adult mice, we found that the defect of Glut3 trafficking was also present in the brain of adult HD140Q/140Q mice.”
Quote in the paperSubstantial claim - Findingown data
HD140Q/140Q neurons display less Glut3 on the cell surface relative to WT neurons.
“Relative to WT neurons, HD140Q/140Q neurons expressed normal levels of Glut3 protein, but displayed less Glut3 on the cell surface, suggesting that there is a deficit of Glut3 trafficking to the cell surface in HD neurons.”
Quote in the paperSubstantial claim - Findingown data
Overall levels of Glut3 protein in primary HD140Q/140Q neurons are comparable to those in WT neurons.
“However, the glucose uptake defect in HD140Q/140Q neurons was unlikely to result from aberrant expression of Glut3 protein because the overall levels of Glut3 protein in primary HD140Q/140Q neurons were comparable to those in WT neurons (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
Similar effects of expressing rab11 mutants on Glut3 trafficking are observed in STHdhQ111/Q111 cells.
“Similar effects of expressing rab11 mutants on Glut3 trafficking were also observed in STHdhQ111/Q111 cells (Figure 3F).”
Quote in the paperSubstantial claim - Findingown data
Glut3 protein expression is up-regulated in STHdhQ111/Q111 cells relative to STHdhQ7/Q7 cells.
“Western blot analysis of post-nuclear supernatants showed up-regulated Glut3 protein expression in STHdhQ111/Q111 cells relative to STHdhQ7/Q7 cells.”
Quote in the paperNot a substantial claim - Findingown data
Glut3 protein levels are normal in the brain of HD 140Q/140Q mice.
“Normal levels of Glut3 protein in HD 140Q/140Q mouse brain.”
Quote in the paperSubstantial claim - Findingown data
Glut3 trafficking is defective in the brain of adult HD 140Q/140Q mice.
“Defective Glut3 trafficking in the brain of adult HD 140Q/140Q mice.”
Quote in the paperSubstantial claim - Interpretationown data
Glut3 trafficking is defective in HD neurons.
“In conclusion, we identify Glut3 as a new cargo protein that is regulated by rab11 during its trafficking to the cell surface and show defective trafficking of Glut3 in HD neurons.”
Quote in the paperSubstantial claim - Interpretationown data
Glut3 trafficking to the cell surface is regulated by rab11.
“Taken together, these data indicate that Glut3 trafficking to the cell surface is regulated by rab11.”
- Also stated in: § Abstract · hedged
“Expression of dominant active and negative rab11 mutants in clonal striatal cells altered the levels of cell surface Glut3 suggesting a regulation by rab11.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · hedged
- Premisecitation
Glut3 is predominantly intracellular in neurons at steady state, as suggested by Ferreira et al.'s data.
“Although not specifically noted by the authors, a predominantly intracellular localization of Glut3 in neurons is suggested by their data, which revealed extremely low levels of Glut3 on neuronal surfaces at steady state [29].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Ferreira JM, Burnett AL, Rameau GA: Activity-dependent regulation of surface glucose transporter-3. (Translated from eng). J Neurosci 2011, 31(6):1991–1999. (in eng) 10.1523/JNEUROSCI.1850-09.2011 source
- Interpretationown data
Impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD.
“These data define Glut3 to be a rab11-dependent trafficking cargo and suggest that impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD.”
- Also stated in: § Introduction · hedged
“Our study suggests that defective Glut3 trafficking arising from compromised activation of rab11 in HD neurons contributes to glucose hypometabolism in HD.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · hedged
- Interpretationcitation
Reduced glucose utilization in early stages of HD is unlikely to result from altered expression of Glut3 protein.
“This suggests that reduced glucose utilization in early stages of HD is unlikely to result from altered expression of Glut3 protein.”
Quote in the paperSubstantial claim - Interpretationreasoning
A Glut3 trafficking deficit arising from compromised activation of rab11 in HD neurons is a cause of energy metabolism disturbance in HD.
“Our study suggests that a Glut3 trafficking deficit arising from compromised activation of rab11 in HD neurons is a cause of energy metabolism disturbance in HD.”
Quote in the paperSubstantial claim- Rests on an assumption: rab11 has diminished activity in HD cells.
- Interpretationreasoning
Glut3 trafficking is impaired in the HD mouse brain.
“Together these data indicate that Glut3 trafficking is impaired in the HD mouse brain.”
Quote in the paperSubstantial claim - Interpretationown data
Glut3 trafficking to cell surfaces is impaired in HD140Q/140Q primary neurons.
“Together, these data suggest that Glut3 trafficking to cell surfaces is impaired in HD140Q/140Q primary neurons.”
Quote in the paperSubstantial claim - Interpretationown data
Glut3 is a new cargo protein that is regulated by rab11 during its trafficking to the cell surface.
“In conclusion, we identify Glut3 as a new cargo protein that is regulated by rab11 during its trafficking to the cell surface and show defective trafficking of Glut3 in HD neurons.”
Quote in the paperSubstantial claim - Interpretationown data
There is a deficit of Glut3 trafficking to the cell surface in HD neurons.
“Relative to WT neurons, HD140Q/140Q neurons expressed normal levels of Glut3 protein, but displayed less Glut3 on the cell surface, suggesting that there is a deficit of Glut3 trafficking to the cell surface in HD neurons.”
Quote in the paperSubstantial claim - Premisecitation
Diminished rab11 activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1.
“Rab11 regulates numerous receptors and transporters trafficking onto cell surfaces; its diminished activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [23] Li X, Sapp E, Chase K, Comer-Tierney LA, Masso N, Alexander J, Reeves P, Kegel KB, Valencia A, Esteves M, Aronin N, Difiglia M: Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease. (Translated from eng). Neurobiol Dis 2009, 36(2):374–383. (in eng) 10.1016/j.nbd.2009.08.003 source
- cites [24] Li X, Standley C, Sapp E, Valencia A, Qin ZH, Kegel KB, Yoder J, Comer-Tierney LA, Esteves M, Chase K, Alexander J, Masso N, Sobin L, Bellve K, Tuft R, Lifshitz L, Fogarty K, Aronin N, DiFiglia M: Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity. (Translated from eng). Mol Cell Biol 2009, 29(22):6106–6116. (in eng) 10.1128/MCB.00420-09 source
- cites [25] Li X, Valencia A, McClory H, Sapp E, Kegel KB, Difiglia M: Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice. (Translated from eng). Biochem Biophys Res Commun 2012, 421(4):727–730. (in eng) 10.1016/j.bbrc.2012.04.070 source
- cites [26] Li X, Valencia A, Sapp E, Masso N, Alexander J, Reeves P, Kegel KB, Aronin N, Difiglia M: Aberrant Rab11-dependent trafficking of the neuronal glutamate transporter EAAC1 causes oxidative stress and cell death in Huntington's disease. (Translated from eng). J Neurosci 2010, 30(13):4552–4561. (in eng) 10.1523/JNEUROSCI.5865-09.2010 source
- Interpretationreasoning
The Glut3 trafficking deficit in HD cells is a result of rab11 dysfunction.
“This Glut3 trafficking deficit is a result of rab11 dysfunction in HD cells.”
Quote in the paperSubstantial claim- Rests on an assumption: rab11 has diminished activity in HD cells.
- Interpretationown data§ Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice
Glut3 transport to the cell surface is reduced in neurons of CAG140 Huntington's disease mice.
“Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice”
Quote in the paperSubstantial claim - Interpretationown data
Glut3 in neurons travels through rab11-positive endosomes.
“These data suggest that Glut3 in neurons travels through rab11-positive endosomes.”
Quote in the paperSubstantial claim - Premisecitation
Rab11 regulates trafficking of numerous receptors and transporters to cell surfaces.
“Rab11 regulates numerous receptors and transporters trafficking onto cell surfaces; its diminished activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1.”
- Also stated in: § Introduction · plain
“Rab11 is a ras-like GTPase that plays a pivotal role in sustaining the homeostatic abundance of receptors, transporters and other critical molecules on the cell surface by regulating vesicle formation at the recycling endosome, vesicle transport along cytoskeleton networks, and vesicle fusion with the plasma membrane [19-22].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [19] Ullrich O, Reinsch S, Urbe S, Zerial M, Parton RG: Rab11 regulates recycling through the pericentriolar recycling endosome. (Translated from eng). J Cell Biol 1996, 135(4):913–924. (in eng) 10.1083/jcb.135.4.913 source
- cites [20] Wilcke M, Johannes L, Galli T, Mayau V, Goud B, Salamero J: Rab11 regulates the compartmentalization of early endosomes required for efficient transport from early endosomes to the trans-golgi network. (Translated from eng). J Cell Biol 2000, 151(6):1207–1220. (in eng) 10.1083/jcb.151.6.1207 source
- cites [21] Correia SS, Bassani S, Brown TC, Lisé MF, Backos DS, El-Husseini A, Passafaro M, Esteban JA: Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation. (Translated from eng). Nat Neurosci 2008, 11(4):457–466. (in eng) 10.1038/nn2063 source
- cites [22] Takahashi S, Kubo K, Waguri S, Yabashi A, Shin HW, Katoh Y, Nakayama K: Rab11 regulates exocytosis of recycling vesicles at the plasma membrane. (Translated from eng). J Cell Sci 2012, 125(Pt 17):4049–4057. (in eng) 10.1242/jcs.102913 source
- Also stated in: § Introduction · plain
- Interpretationown data
Glut3 travels through rab11-positive endosomes.
“These data indicate that Glut3 travels through rab11-positive endosomes.”
Quote in the paperSubstantial claim - Interpretationown data
The glucose uptake defect in HD140Q/140Q neurons is unlikely to result from aberrant expression of Glut3 protein.
“However, the glucose uptake defect in HD140Q/140Q neurons was unlikely to result from aberrant expression of Glut3 protein because the overall levels of Glut3 protein in primary HD140Q/140Q neurons were comparable to those in WT neurons (Figure 1A).”
Quote in the paperSubstantial claim - Interpretationown data
rab11 regulates the cell surface expression of Glut3.
“The findings in this study show that rab11, which is known to have diminished activity in HD cells, regulates the cell surface expression of Glut3, the major transporter for glucose uptake in neurons.”
- Also stated in: § Rab11 modulates Glut3 trafficking to the cell surface · plain
“Figure 3 Rab11 regulates Glut3 trafficking.”
Quote in the paperSubstantial claim- Rests on an assumption: Glut3 is the major transporter for glucose uptake in neurons.
- Rests on an assumption: rab11 has diminished activity in HD cells.
- Also stated in: § Rab11 modulates Glut3 trafficking to the cell surface · plain
- Interpretationown data
Glut3 is a rab11-dependent trafficking cargo.
“These data define Glut3 to be a rab11-dependent trafficking cargo and suggest that impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD.”
Quote in the paperSubstantial claim
- The quote only partly states this claim. 1
- It may state two separate claims as one. 13
- Probably not a substantial claim. 11
The quote only partly states this claim.
Findingown dataIn primary cortical neurons, Glut3 and rab11 co-localize in neurites and somata.
“Some structures were immunoreative for both Glut3 and rab11 (Figure 2A).”
- Also stated in: § Glut3 traffics through recycling endosomes · plain
“Quantitative analysis revealed that 35.3 ± 10.7% of Glut3 labeled puncta in the neurites also contained rab11, and 44.4 ± 9.5% of rab11 positive puncta were also positive for Glut3 (Mean ± SD, n = 20 neurite segments from 20 different neurons).”
Quote in the paperSubstantial claim- Also stated in: § Glut3 traffics through recycling endosomes · plain
It may state two separate claims as one.
Findingown dataGlut3 is co-localized with rab11 in neurites and somata of primary cortical neurons and is recovered in brain endosomes immuno-isolated using antibodies specific for rab11.
“We found that Glut3 was co-localized with rab11 in neurites and somata of primary cortical neurons and was recovered in brain endosomes immuno-isolated using antibodies specific for rab11.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataEndogenous Glut3 in immortalized striatal cells co-localizes with rab11 and is localized mainly inside cells.
“In addition, immortalized striatal cells expressed endogenous Glut3, which was co-localized with rab11 and localized mainly inside of cells (Figure 3C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataViral expression of permanently active or inactive rab11 respectively alters cell surface expression of Glut3 with no effect on overall expression levels of Glut3 protein.
“Viral expression of permanently active or inactive rab11 respectively altered cell surface expression of Glut3 with no effect on overall expression levels of Glut3 protein.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn subcellular fractionation of WT mouse brain, Glut3 signal is present in several fractions and peaks in fraction-5, which is also enriched in rab11.
“Western blot analysis showed that Glut3 signal was present in several fractions and peaked in fraction-5, in which rab11 was also enriched (Figure 2B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn STHdhQ7/Q7 cells, expression of dominant active rab11 (dArab11) increases cell surface Glut3, while expression of dominant negative rab11 (dNrab11) decreases cell surface Glut3.
“However, levels of biotinylated cell surface Glut3 were significantly increased in cells expressing dArab11 and decreased in cells expressing dNrab11 (Figure 3D and E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationThe HD mutation reduces the production of active rab11, thereby slowing endosomal recycling of receptors and transporters to the cell surface.
“The HD mutation is known to reduce the production of active rab11, thereby slowing endosomal recycling of receptors and transporters to the cell surface [23-26].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [23] Li X, Sapp E, Chase K, Comer-Tierney LA, Masso N, Alexander J, Reeves P, Kegel KB, Valencia A, Esteves M, Aronin N, Difiglia M: Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease. (Translated from eng). Neurobiol Dis 2009, 36(2):374–383. (in eng) 10.1016/j.nbd.2009.08.003 source
- cites [24] Li X, Standley C, Sapp E, Valencia A, Qin ZH, Kegel KB, Yoder J, Comer-Tierney LA, Esteves M, Chase K, Alexander J, Masso N, Sobin L, Bellve K, Tuft R, Lifshitz L, Fogarty K, Aronin N, DiFiglia M: Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity. (Translated from eng). Mol Cell Biol 2009, 29(22):6106–6116. (in eng) 10.1128/MCB.00420-09 source
- cites [25] Li X, Valencia A, McClory H, Sapp E, Kegel KB, Difiglia M: Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice. (Translated from eng). Biochem Biophys Res Commun 2012, 421(4):727–730. (in eng) 10.1016/j.bbrc.2012.04.070 source
- cites [26] Li X, Valencia A, Sapp E, Masso N, Alexander J, Reeves P, Kegel KB, Aronin N, Difiglia M: Aberrant Rab11-dependent trafficking of the neuronal glutamate transporter EAAC1 causes oxidative stress and cell death in Huntington's disease. (Translated from eng). J Neurosci 2010, 30(13):4552–4561. (in eng) 10.1523/JNEUROSCI.5865-09.2010 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationHeterozygous Glut3-deficient mice show brain developmental characteristics seen in autism spectrum disorders, including abnormal cognitive flexibility with intact motor ability, perturbed social behavior with reduced vocalization and stereotypies, and seizures.
“While they can survive, heterozygous Glut3-deficient mice show brain developmental characteristics seen in autism spectrum disorders such as abnormal cognitive flexibility with intact motor ability, perturbed social behavior with reduced vocalization and stereotypies, and seizures [42].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Zhao Y, Fung C, Shin D, Shin BC, Thamotharan S, Sankar R, Ehninger D, Silva A, Devaskar SU: Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders. (Translated from eng). Mol Psychiatry 2010, 15(3):286–299. (in eng) 10.1038/mp.2009.51 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationHomozygous Glut3 deficient mice die prenatally.
“Homozygous Glut3 deficient mice die prenatally [41].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Ganguly A, McKnight RA, Raychaudhuri S, Shin BC, Ma Z, Moley K, Devaskar SU: Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction. (Translated from eng). Am J Physiol Endocrinol Metab 2007, 292(5):E1241-E1255. (in eng) 10.1152/ajpendo.00344.2006 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGlut3 is mainly intracellular in platelets.
“The mainly intracellular localization of Glut3 is also observed in platelets [34].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Heijnen HF, Oorschot V, Sixma JJ, Slot JW, James DE: Thrombin stimulates glucose transport in human platelets via the translocation of the glucose transporter GLUT-3 from alpha-granules to the cell surface. J Cell Biol 1997, 138(2):323–330. 10.1083/jcb.138.2.323 source
It may state two separate claims as one.
Study design and conductown dataIn the biotinylation assay, cell surface proteins were efficiently biotinylated, as shown by the majority of NCAM being biotinylated and actin being mainly unbiotinylated.
“As expected, the majority of NCAM molecules were biotinylated, whereas actin was mainly unbiotinylated (Figure 1C), indicating that cell surface proteins were efficiently biotinylated.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationPrimary HD140Q/140Q cortical neurons have a deficit in taking up glucose that can be attenuated by expression of active rab11.
“In a previous study we showed that primary HD140Q/140Q cortical neurons have a deficit in taking up glucose, which can be attenuated upon expression of active rab11 [25].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Li X, Valencia A, McClory H, Sapp E, Kegel KB, Difiglia M: Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice. (Translated from eng). Biochem Biophys Res Commun 2012, 421(4):727–730. (in eng) 10.1016/j.bbrc.2012.04.070 source
Probably not a substantial claim. It may state two separate claims as one.
Study design and conductown dataThe data were obtained from digital images of 12 microscopic fields of 6 WT and 6 HD brain sections from 2 WT and 2 HD mice, which were treated under exactly the same conditions.
“The data were obtained from digital images of 12 microscopic fields of 6 WT and 6 HD brain sections from 2 WT and 2 HD mice, which were treated under exactly the same conditions.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn other cell types or in conditions of overexpression, Glut3 can locate mainly at plasma membranes.
“However, in other cell types or in conditions of overexpression Glut3 can locate mainly at plasma membranes [12,35].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12] Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ: The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 2008, 295(2):E242-E253. 10.1152/ajpendo.90388.2008 source
- cites [35] Cidad P, Almeida A, Bolanos JP: Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5'-AMP-activated protein kinase. Biochem J 2004, 384(Pt 3):629–636. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationTransient exposure of cerebellar granule neurons to glutamate vastly increases the expression of Glut3 on the cell surface without altering total levels of Glut3 protein.
“Transient exposure of cerebellar granule neurons to glutamate vastly increases the expression of Glut3 on the cell surface without altering total levels of Glut3 protein [36].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Weisova P, Concannon CG, Devocelle M, Prehn JH, Ward MW: Regulation of glucose transporter 3 surface expression by the AMP-activated protein kinase mediates tolerance to glutamate excitation in neurons. J Neurosci 2009, 29(9):2997–3008. 10.1523/JNEUROSCI.0354-09.2009 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenDigital images were analyzed by an examiner who was blinded to the conditions.
“Digital images were analyzed using NIH ImageJ by an examiner who was blinded to the conditions.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationStimuli that activate NMDA receptors induce Glut3 translocation from intracellular compartments to cell surfaces.
“Stimuli that activate NMDA receptors induce Glut3 translocation from intracellular compartments to cell surfaces [29].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Ferreira JM, Burnett AL, Rameau GA: Activity-dependent regulation of surface glucose transporter-3. (Translated from eng). J Neurosci 2011, 31(6):1991–1999. (in eng) 10.1523/JNEUROSCI.1850-09.2011 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPositron emission tomography with [18F]-fluorodeoxyglucose reveals a regional decrease of glucose usage in the striatum and cortex of persons symptomatic and at risk for HD.
“Positron emission tomography brain imaging with [18 F]-fluorodeoxyglucose has revealed a regional decrease of glucose usage in the striatum (caudate and putamen) and cortex (frontal and temporal lobes) of persons symptomatic and at risk for HD [3-8].”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [3] Kuhl DE, Phelps ME, Markham CH, Metter EJ, Riege WH, Winter J: Cerebral metabolism and atrophy in Huntington's disease determined by 18FDG and computed tomographic scan. Ann Neurol 1982, 12(5):425–434. 10.1002/ana.410120504 source
- cites [4] Hayden MR, Martin WRW, Stoessl AJ, Clark C, Hollenberg S, Adam MJ, Ammann W, Harrop R, Rogers J, Ruth T, Sayre C, Pate BD: Positron emission tomography in the early diagnosis of Huntington's disease. Neurology 1986, 36(7):888–894. 10.1212/WNL.36.7.888 source
- cites [5] Young AB, Penney JB, Starosta-Rubinstein S, Markel DS, Berent S, Giordani B, Ehrenkaufer R, Jewett D, Hichwa R: PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol 1986, 20(3):296–303. 10.1002/ana.410200305 source
- cites [6] Kuwert T, Lange HW, Langen KJ, Herzog H, Aulich A, Feinendegen LE: Cortical and subcortical glucose consumption measured by PET in patients with Huntington's disease. Brain 1990, 113(Pt 5):1405–1423. 10.1093/brain/113.5.1405 source
- cites [7] Martin WR, Clark C, Ammann W, Stoessl AJ, Shtybel W, Hayden MR: Cortical glucose metabolism in Huntington's disease. Neurology 1992, 42(1):223–229. 10.1212/WNL.42.1.223 source
- cites [8] Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, Squitieri F: Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease. J Nucl Med 2006, 47(2):215–222.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationEnergy deficiency in HD involves an extra-mitochondrial pathway, as suggested by studies in immortalized STHdhQ111/Q111 striatal cells.
“Studies in immortalized STHdhQ111/Q111 striatal cells suggest that energy deficiency in HD involves an extra-mitochondrial pathway [33].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Lee JM, Ivanova EV, Seong IS, Cashorali T, Kohane I, Gusella JF, MacDonald ME: Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet 2007, 3(8):e135. 10.1371/journal.pgen.0030135 source
It may state two separate claims as one.
PremisecitationHD patients at early stages of striatal degeneration (grade I) have normal levels of Glut3 protein but show a decline in glucose utilization in the brain.
“HD patients at early stages of striatal degeneration (grade I [17]) have normal levels of Glut3 protein, but show a decline in glucose utilization in the brain [3,8,18].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [17] Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr: Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 1985, 44(6):559–577. 10.1097/00005072-198511000-00003 source
- cites [3] Kuhl DE, Phelps ME, Markham CH, Metter EJ, Riege WH, Winter J: Cerebral metabolism and atrophy in Huntington's disease determined by 18FDG and computed tomographic scan. Ann Neurol 1982, 12(5):425–434. 10.1002/ana.410120504 source
- cites [8] Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, Squitieri F: Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease. J Nucl Med 2006, 47(2):215–222.
- cites [18] Gamberino WC, Brennan WA Jr: Glucose transporter isoform expression in Huntington's disease brain. J Neurochem 1994, 63(4):1392–1397. 10.1046/j.1471-4159.1994.63041392.x source
Probably not a substantial claim. It may state two separate claims as one.
Study design and conductreasoningOmitting detergents in all buffer solutions preserved the intactness of the plasma membrane, ensuring that anti-Glut3 and anti-GABAα1 antibodies labeled only cell surface molecules.
“To ascertain that anti-Glut3 and anti-GABAα1 antibodies labeled only cell surface molecules, we omitted detergents in all buffer solutions used for this assay to preserve the intactness of the plasma membrane.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The mechanism underlying reduced glucose usage in HD is poorly understood.
“However, the mechanism underlying reduced glucose usage is poorly understood.”
The paper relies on this without support.
Deficient energy metabolism is a hallmark in the pathogenesis of HD and may arise from multiple factors including reduced glucose utilization in the brain.
“Deficient energy metabolism is a hallmark in the pathogenesis of HD and may arise from multiple factors including reduced glucose utilization in the brain.”
The paper relies on this without support.
The subcellular localization of Glut3 in neurons was not formally investigated previously.
“The subcellular localization of Glut3 in neurons was not formally investigated previously.”
The paper relies on this without support.
Glut3 is the major transporter for glucose uptake in neurons.
“the major transporter for glucose uptake in neurons”
The paper relies on this without support.
rab11 has diminished activity in HD cells.
“which is known to have diminished activity in HD cells”
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Self-citation
Metadata
- Authors
- McClory, H., Williams, D., Sapp, E., Gatune, L. W., Wang, P., DiFiglia, M., & Li, X.
- Affiliations
- Harvard University (US)
- Second Hospital of Shandong University (CN)
- Corresponding author
- Li, Xueyi
- Venue
- Acta Neuropathologica Communications
- Published
- 2014-12
- Volume
- 2
- Issue
- 1
- Pages
- 179-179
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4297405
- OpenAlex
- W2160410868
- Cited by
- 60
- References
- 42
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 11 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 5 · 2015: 4
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Hereditary Disease Foundation
- CHDI Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS074381)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- GLUT3, Rab11, Huntington's disease, neuronal glucose uptake, cell surface trafficking, endosomes, striatal neurons, glucose hypometabolism
- MeSH terms
- Huntingtin Protein, rab11 GTP-Binding Proteins, Animals, Cell Membrane, Cells, Cultured, Cerebral Cortex, Corpus Striatum, Disease Models, Animal, Humans, Huntington Disease, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Receptors, GABA-A, Endosomes, rab GTP-Binding Proteins, Protein Transport, Glucose Transporter Type 3, Gene Knock-In Techniques
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