Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk
Open accessAbstract
Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith–Lemli–Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte–microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte–microglia immune axis, with possible implications in other neurological diseases.
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Written from the paper’s full text.
TL;DR
In a hypomorphic mouse model of Smith–Lemli–Opitz syndrome, Dhcr7 mutant astrocytes show morphological, lipid-droplet, and transcriptional signs of immune reactivity, but this state is not astrocyte-intrinsic. Dhcr7 mutant microglia are themselves reactive and drive astrocyte activation in co-culture, with downstream astrocyte hyper-responsiveness to glutamate and altered calcium signaling.
Key findings
- Dhcr7 astrocytes cultured 7 days in lipoprotein-deficient serum showed increased cell area and GFAP intensity (n=9 wells for area, n=12 for GFAP intensity; three biological replicates, mean of 40 images/well) and increased BODIPY lipid-droplet intensity and spot area (n=75 cells/group; three biological replicates, five images/replicate). GFAP intensity was also increased in vivo at P7 and P30.
- Dhcr7 astrocytes had increased reactive astrocyte transcripts, including Gbp2 and Ptx3, in vitro and in P7/P30 cortex in vivo, with evidence of distinct reactive subtypes.
- Dhcr7 astrocytes showed reduced baseline calcium activity, hyper-responsive calcium signaling after 3 µM glutamate but not 3 µM ATP, and increased EAAT1 protein in brain lysates (n=4 biological replicates).
- Pharmacological cholesterol-synthesis inhibition with AY9944 (5 µM), U18666A (20 nM), or atorvastatin (2.5 µM) produced morphological changes but muted transcriptional reactivity, suggesting Dhcr7 astrocyte reactivity is not astrocyte-intrinsic. Dhcr7 microglia showed increased cell area, CD68 expression, reactive transcripts, and BODIPY accumulation; co-culture of control human astrocytes with Dhcr7 mouse microglia increased GFAP intensity, cell area, lipid droplets, and some reactive transcripts.
Methods
- Primary glia were isolated from P2–P5 cerebral cortices of Dhcr7Δ3-5/T93M mice and Dhcr7WT/T93M controls, cultured for 21 days, then microglia were separated by shaking; astrocytes were purified and cultured in LPDS for 7 days to force endogenous cholesterol synthesis. Human primary cortical astrocytes were used for co-culture with mouse microglia.
- Analyses included high-content imaging, immunocytochemistry/immunohistochemistry, RNAscope in situ hybridization, qRT-PCR, GC/MS sterol analysis, Western blotting, and live-cell calcium imaging with Fluo-4 AM and 3 µM glutamate or 3 µM ATP.
- Statistics used unpaired two-tailed t-tests or one-way ANOVA with Dunnett’s post hoc test versus LPDS controls, with P<0.05 considered significant.
Limitations
- The paper states that the exact mechanisms of microglial cholesterol synthesis are unknown, whether Dhcr7 microglia are self-reactive versus responding to external stimuli is unanswered, and future cell-specific Dhcr7 deletion, immunopanning, and single-cell RNA-sequencing are needed.
- The paper notes the Dhcr7Δ3-5/T93M model is hypomorphic with reduced disease severity, and that co-culture experiments showed only some, not all, reactive transcripts changed in astrocytes.
- Evident from the text: conclusions rely heavily on primary in vitro cultures under LPDS conditions, the key co-culture uses mouse microglia with human astrocytes, and pharmacological inhibition did not fully recapitulate the genetic model, leaving the causal pathway unresolved.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
19 of 32 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The presence of the blood-brain barrier requires cholesterol in the brain to be synthesized de novo, primarily by astrocytes.
“However, the presence of the blood–brain barrier requires cholesterol in the brain to be synthesized de novo, primarily by astrocytes (Jeske and Dietschy, 1980; Mahley, 2016).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Jeske and Dietschy, 1980 source
- cites Mahley, 2016 source
The Abstract says the blood–brain barrier restricts cholesterol entry and identifies astrocytes among the cells that synthesize CNS cholesterol. The ‘Cholesterol Synthesis and Metabolism in the CNS’ section says brain cholesterol is synthesized in situ and that adult production comes from glial cells and, to a lesser extent, neurons. Neither passage establishes that astrocytes specifically are the primary producers. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Disruption of cholesterol biosynthesis in astrocytes alone directly impairs neurite outgrowth and synapse formation.
“Previous work identified a direct impairment of neurite outgrowth and synapse formation when cholesterol biosynthesis was disrupted in astrocytes alone, further highlighting the importance of astrocyte health and function in the context of neurodevelopment (Ferris et al., 2017).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Ferris et al., 2017 source
The neurite-outgrowth section reports reduced neurite growth when neurons were cocultured with SREBP2-knockdown glial cells. The Discussion links astrocyte cholesterol loss to reduced synapse quality and quantity as an inference, but does not report a direct measurement of impaired synapse formation. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Interpretationcitation
Microglia cholesterol synthesis plays a critical role in promoting normal microglia function.
“Our work, which suggests a critical role for microglia cholesterol synthesis in promoting normal microglia function, agrees with recently published work in multiple sclerosis and Alzheimer's disease (Berghoff et al., 2021; Tcw et al., 2022).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Berghoff et al., 2021 source
The Results section ('The origin of cholesterol for remyelination depends on the disease phase'; page unavailable) reports that blocking sterol synthesis in microglia/macrophages severely impaired remyelination after acute demyelination. The Discussion links sterol synthesis to cholesterol recycling and suppression of inflammation. These findings support a role in microglial function during lesion repair, but not the broader claim that cholesterol synthesis is critical for normal microglial function under physiological conditions. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Tcw et al., 2022 source
The Results section on impaired cholesterol trafficking reports altered cholesterol synthesis in APOE4 microglia and reduced myelin uptake, a microglial function. The Discussion also links microglial lipid dysregulation to impaired debris recycling and inflammation. These findings support a connection between cholesterol metabolism and microglial function, but do not establish that cholesterol synthesis itself is critical for promoting normal function. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Findingown data
Astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of GFAP and cellular hypertrophy.
“We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy.”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 mutant astrocytes exhibit altered calcium flux.
“Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux.”
Quote in the paperNot a substantial claim
- Findingown data
Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation.
“Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux.”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 mutant astrocytes are hyper-responsive to glutamate stimulation.
“Dhcr7 mutant astrocytes exhibited a hyperactive calcium response following glutamate stimulation (Fig. 4E,F).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 mutant astrocytes exhibit a hyperactive calcium response following glutamate stimulation.
“Dhcr7 mutant astrocytes exhibited a hyperactive calcium response following glutamate stimulation (Fig. 4E,F).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 mutant astrocytes display reduced baseline calcium activity compared to controls.
“Dhcr7 mutant astrocytes displayed reduced baseline activity in comparison to controls (Fig. 4C,D).”
Quote in the paperNot a substantial claim - Findingown data
Human primary astrocytes cultured with Dhcr7 mutant microglia display increased accumulation of BODIPY-labeled lipid droplets.
“Consistent with this reactive state, human primary astrocytes cultured with Dhcr7 mutant microglia also displayed increased accumulation of BODIPY-labeled lipid droplets (Fig. S6A-C).”
Quote in the paperNot a substantial claim - Findingown data
BODIPY spot intensity is increased in Dhcr7 mutant samples.
“Both BODIPY spot intensity (Fig. 1G) and spot size (Fig. 1F) were increased in Dhcr7 mutant samples.”
Quote in the paperSubstantial claim - Findingown data
CD68 and Iba1 intensity is increased in Dhcr7 brains at both P7 and P30.
“Analysis of CD68 and Iba1 intensity showed an increase at both timepoints (Fig. 6F,G).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 mutant astrocytes exhibit robust increases in expression of previously identified reactive astrocyte transcripts.
“Dhcr7 mutant astrocytes exhibited robust increases in expression of previously identified reactive astrocyte transcripts (Fig. 2B; Table S2) (Liddelow et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liddelow et al., 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
BODIPY spot size is increased in Dhcr7 mutant samples.
“Both BODIPY spot intensity (Fig. 1G) and spot size (Fig. 1F) were increased in Dhcr7 mutant samples.”
Quote in the paperSubstantial claim - Findingown data
Increased expression of Gbp2 and Ptx3 is detected at both P7 and P30 in Dhcr7 mice in vivo.
“Increased expression of Gbp2 and Ptx3 was detected at both timepoints in Dhcr7 mice in vivo (Fig. 3C,D,G,H).”
Quote in the paperSubstantial claim - Findingown data
Increased expression of both Gbp2 and Ptx3 reactive transcripts is identified in Dhcr7 astrocytes.
“Increased expression of both Gbp2 and Ptx3 reactive transcripts was identified in Dhcr7 astrocytes, although distinct reactive subtypes appeared to exist in Dhcr7 astrocyte cultures (Fig. 2D,E).”
Quote in the paperSubstantial claim - Findingown data
Human astrocytes co-cultured with Dhcr7 microglia show increased GFAP intensity.
“Following co-culture and immunolabeling with GFAP, quantitative analyses showed increased cell area and GFAP intensity in human astrocytes co-cultured with Dhcr7 microglia (Fig. 7B-D).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 astrocytes display a significant increase in cellular area.
“Dhcr7 astrocytes were immunolabeled with GFAP and CellMask Blue stain (Fig. 1B), displaying a significant increase in both cellular area and GFAP intensity (Fig. 1C,D), suggestive of astrocyte reactivity.”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 microglia exhibit a transcriptional signature indicative of reactivity.
“Dhcr7 microglia exhibited a transcriptional signature indicative of reactivity (Fig. 6D; Table S2) coupled with increased BODIPY accumulation (Fig. S5A-C) (Liddelow et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liddelow et al., 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
The hyper-responsive phenotype is not recapitulated following stimulation with ATP.
“This hyper-responsive phenotype was not recapitulated following stimulation with ATP, suggesting the presence of a glutamate-specific mechanism (Fig. S2B,C).”
Quote in the paperSubstantial claim - Findingown data
Human astrocytes exhibit increased expression of reactive astrocyte transcripts following co-culture with Dhcr7 microglia.
“Using this method, human astrocytes exhibited increased expression of reactive astrocyte transcripts following co-culture with Dhcr7 microglia (Fig. 7E).”
Quote in the paperSubstantial claim - Findingcitation
Dhcr7 microglia exhibit increased BODIPY accumulation.
“Dhcr7 microglia exhibited a transcriptional signature indicative of reactivity (Fig. 6D; Table S2) coupled with increased BODIPY accumulation (Fig. S5A-C) (Liddelow et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liddelow et al., 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
Trpc4 expression is significantly reduced in Dhcr7 mutant mice.
“Additional analysis of Trpc4 expression, a key regulator of store-operated calcium entry, showed a significant reduction in Dhcr7 mutant mice (Fig. S2A).”
Quote in the paperNot a substantial claim - Findingown data
Pharmacological inhibition of cholesterol synthesis does not recapitulate the reactive transcript expression observed in Dhcr7 astrocytes.
“Although pharmacological inhibition of cholesterol synthesis resulted in hallmark morphological changes observed upon astrocyte activation (Fig. 5B), including cellular hypertrophy and increased GFAP intensity (Fig. 5C,D), the expression of reactive transcripts was not consistent with our findings in Dhcr7 astrocytes (Fig. 5E).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 mutant mice display an increase in EAAT1 protein expression in brain lysates.
“Dhcr7 mutant mice also displayed an increase in EAAT1 protein expression in brain lysates (Fig. 4G).”
Quote in the paperNot a substantial claim - Findingown data
Dysregulation of cholesterol metabolism induces a reactive state in Dhcr7 astrocytes and microglia, characterized by morphological and transcriptional changes.
“In this study, we demonstrate that dysregulation of cholesterol metabolism induces a reactive state in Dhcr7 astrocytes and microglia, characterized by both morphological and transcriptional changes.”
Quote in the paperSubstantial claim - Findingown data
Inhibition of cholesterol synthesis in control human primary astrocytes shows comparable biochemical defects and morphological changes to those observed in control mouse astrocytes treated with small-molecule inhibitors.
“To confirm that this was not a species-specific difference, inhibition of cholesterol synthesis in control human primary astrocytes showed comparable biochemical defects (Fig. S4A) and morphological changes similar to those observed in control mouse astrocytes treated with small-molecule inhibitors of cholesterol synthesis (Fig. S4B-D).”
Quote in the paperNot a substantial claim - Findingown data
Dhcr7 microglia exhibit increased CD68 expression per cell.
“Following purification of microglia from mixed glial cultures, immunolabeling for CD68 and CellMask Blue staining showed both increased cell area and CD68 expression per cell in Dhcr7 microglia, regardless of culture conditions (Fig. 6A-C).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 microglia exhibit increased cell area.
“Following purification of microglia from mixed glial cultures, immunolabeling for CD68 and CellMask Blue staining showed both increased cell area and CD68 expression per cell in Dhcr7 microglia, regardless of culture conditions (Fig. 6A-C).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 astrocytes display accumulation of BODIPY-labeled lipid droplets.
“Dhcr7 astrocytes also displayed another reactive cellular phenotype, accumulation of BODIPY-labeled lipid droplets (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data
Atorvastatin-treated astrocytes trend similarly to AY9944-treated astrocytes for both immunocytochemistry and qRT-PCR assays.
“Additionally, atorvastatin-treated astrocytes trended similarly to AY9944-treated astrocytes for both the immunocytochemistry and qRT-PCR assays (Fig. 5B-E), suggesting that reduction of cholesterol plays a larger role in these cellular changes than does accumulation of 7-DHC.”
Quote in the paperSubstantial claim - Findingown data
Human astrocytes co-cultured with Dhcr7 microglia show increased cell area.
“Following co-culture and immunolabeling with GFAP, quantitative analyses showed increased cell area and GFAP intensity in human astrocytes co-cultured with Dhcr7 microglia (Fig. 7B-D).”
Quote in the paperSubstantial claim - Findingown data
Dhcr7 astrocytes display a significant increase in GFAP intensity.
“Dhcr7 astrocytes were immunolabeled with GFAP and CellMask Blue stain (Fig. 1B), displaying a significant increase in both cellular area and GFAP intensity (Fig. 1C,D), suggestive of astrocyte reactivity.”
Quote in the paperSubstantial claim - Findingnone given
Reactive astrocytes display functional deficits in glutamate-dependent calcium signaling.
“Lastly, reactive astrocytes also display functional deficits in glutamate-dependent calcium signaling.”
Quote in the paperSubstantial claim - Findingown data
GFAP intensity is increased in the Dhcr7 cortex at P7 and P30.
“Analysis of GFAP intensity showed an increase at both timepoints (Fig. 3B,F).”
Quote in the paperSubstantial claim - Interpretationown data
Astrocyte-microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis.
“Our data suggest that astrocyte–microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis.”
Quote in the paperSubstantial claim - Interpretationown data
The impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia.
“We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia.”
Quote in the paperSubstantial claim - Interpretationown data
The hyper-responsive phenotype suggests the presence of a glutamate-specific mechanism.
“This hyper-responsive phenotype was not recapitulated following stimulation with ATP, suggesting the presence of a glutamate-specific mechanism (Fig. S2B,C).”
Quote in the paperSubstantial claim - Interpretationown data
Dhcr7 astrocytes exhibit a characteristic transcriptional signature suggestive of a mixed population of reactive subtypes.
“These data demonstrate that Dhcr7 astrocytes exhibit a characteristic transcriptional signature that is suggestive of a mixed population of reactive subtypes.”
Quote in the paperSubstantial claim - Interpretationown data
Glial activity is regulated by Dhcr7.
“Use of co-culture models demonstrated that astrocyte activation primarily occurs due to Dhcr7 microglia, providing novel evidence that glial activity is regulated by Dhcr7.”
Quote in the paperSubstantial claim - Interpretationown data
This reactive astrocyte state is coupled with downstream impacts on astrocytic function, including glutamate uptake and calcium signaling.
“This reactive astrocyte state is coupled with downstream impacts on astrocytic function, including glutamate uptake and calcium signaling.”
Quote in the paperSubstantial claim - Interpretationown data
Mixed populations of astrocyte subtypes are present within this developmental disorder.
“Additionally, the identification of mixed populations of astrocyte subtypes (based upon the expression patterns of transcripts consistent with different reactive astrocyte states) within this developmental disorder is a unique finding.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia have a direct role in driving glial reactivity following Dhcr7 disruption.
“These data demonstrate a direct role for microglia in driving glial reactivity following Dhcr7 disruption, suggesting that microglia cholesterol biosynthesis is required to suppress immune reactivity.”
Quote in the paperSubstantial claim - Interpretationown data
Reduction of cholesterol plays a larger role in these cellular changes than does accumulation of 7-DHC.
“Additionally, atorvastatin-treated astrocytes trended similarly to AY9944-treated astrocytes for both the immunocytochemistry and qRT-PCR assays (Fig. 5B-E), suggesting that reduction of cholesterol plays a larger role in these cellular changes than does accumulation of 7-DHC.”
Quote in the paperSubstantial claim - Interpretationown data
Dhcr7 mutant astrocytes are reactive in response to their exposure to reactive microglia.
“In summary, we have demonstrated that Dhcr7 mutant astrocytes are reactive in response to their exposure to reactive microglia.”
Quote in the paperSubstantial claim - Interpretationown data
Disruption of cholesterol synthesis triggers a stress response in microglia, causing microglia reactivity.
“Our findings suggest that disruption of cholesterol synthesis triggers a stress response in microglia, causing microglia reactivity.”
Quote in the paperSubstantial claim - Interpretationown data
Cholesterol biosynthesis and metabolism appear critical for the suppression of reactive glial states.
“Based upon the transcriptional profiles identified in Dhcr7 mutant astrocytes and microglia, cholesterol biosynthesis and metabolism appear critical for the suppression of reactive glial states.”
Quote in the paperSubstantial claim - Interpretationown data
Dhcr7 loss results in a morphological change accompanied by lipid droplet accumulation that is characteristic of astrocyte immune reactivity.
“These data demonstrate that Dhcr7 loss results in a morphological change accompanied by lipid droplet accumulation that is characteristic of astrocyte immune reactivity.”
Quote in the paperSubstantial claim - Interpretationown data
Reactive Dhcr7 microglia might be an impactful contributor to astrocyte reactivity within this model.
“Based upon these findings, reactive Dhcr7 microglia might be an impactful contributor to astrocyte reactivity within this model.”
Quote in the paperSubstantial claim - Interpretationown data
Reactive microglia drive reactive astrogliosis in Dhcr7 models.
“Additionally, co-culture assays determined that reactive microglia drive reactive astrogliosis in Dhcr7 models.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia cholesterol biosynthesis is required to suppress immune reactivity.
“These data demonstrate a direct role for microglia in driving glial reactivity following Dhcr7 disruption, suggesting that microglia cholesterol biosynthesis is required to suppress immune reactivity.”
Quote in the paperSubstantial claim - Interpretationown data
Distinct reactive astrocyte subtypes appear to exist in Dhcr7 astrocyte cultures.
“Increased expression of both Gbp2 and Ptx3 reactive transcripts was identified in Dhcr7 astrocytes, although distinct reactive subtypes appeared to exist in Dhcr7 astrocyte cultures (Fig. 2D,E).”
Quote in the paperNot a substantial claim - Interpretationown data
Dhcr7 astrocyte reactivity is likely not astrocyte intrinsic but the result of exposure to other factors or cell types.
“These data suggest that Dhcr7 astrocyte reactivity is likely not astrocyte intrinsic but the result of exposure to other factors or cell types.”
Quote in the paperSubstantial claim - Interpretationown data
Cholesterol homeostasis plays a role in mitigating microglial-induced astrocyte immune activation.
“Herein, we have presented evidence supporting a role for cholesterol homeostasis in mitigating microglial-induced astrocyte immune activation.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocyte activation primarily occurs due to Dhcr7 microglia.
“Use of co-culture models demonstrated that astrocyte activation primarily occurs due to Dhcr7 microglia, providing novel evidence that glial activity is regulated by Dhcr7.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 20
- May combine two claims. 20
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn response to injury or disease, astrocytes commonly mount a neuroinflammatory response, which induces a reactive cellular state.
“In response to injury or disease, astrocytes commonly mount a neuroinflammatory response, which then induces a reactive cellular state (Sofroniew and Vinters, 2010; Zamanian et al., 2012).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Sofroniew and Vinters, 2010 source
The paper’s section on descriptive features of reactive astrogliosis says astrocytes undergo reactive changes in response to CNS injury and disease. Its section on CNS inflammation says reactive astrocytes can regulate inflammation in either a pro- or anti-inflammatory direction. It does not support the claimed sequence in which astrocytes first mount a neuroinflammatory response that then induces their reactive state. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Zamanian et al., 2012 source
The Introduction says reactive astrogliosis is a response to brain injury and disease. The Discussion section on inducing stimuli describes immune-system signals as one possible trigger and says reactive astrocytes interact with immune cells; it does not establish that astrocytes first mount a neuroinflammatory response that then induces their reactive state. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAstrocytes support neurite outgrowth, neuronal survival, synapse formation and synaptic pruning, all vital during brain development.
“As the most numerous cell type in the mammalian brain, astrocytes support neurite outgrowth, neuronal survival, synapse formation and synaptic pruning, all of which are vital during brain development (Chung et al., 2013; Clarke and Barres, 2013).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Chung et al., 2013 source
The Concluding Remarks (page not provided) state that astrocytes contribute to synapse elimination and neural circuit refinement in the developing CNS, supporting the synaptic-pruning part of the claim. The passages found in our copy do not establish that astrocytes support neurite outgrowth, neuronal survival, or synapse formation; the reported numerical comparison concerns astrocytes versus microglia in the developing LGN, not whether astrocytes are the most numerous cell type throughout the mammalian brain. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Clarke and Barres, 2013 source
The Conclusions and future perspectives section says astrocytes control synapse formation and elimination, and the Astrocyte control of synapse pruning section places elimination during brain development. The passages found do not establish that astrocytes are the most numerous mammalian brain cell type or directly support the attributed roles in neurite outgrowth and neuronal survival; those terms appear chiefly in reference titles. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAstrocytes supply cholesterol to neurons through transport of apolipoprotein E (APOE) particles.
“Additionally, astrocytes supply cholesterol to neurons through the transport of apolipoprotein E (APOE) particles (Vance, 2012).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Vance, 2012 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLoss of cholesterol homeostasis is implicated in numerous neurological disorders, including autism spectrum disorder.
“Additionally, loss of cholesterol homeostasis has been implicated in numerous neurological disorders, including autism spectrum disorder (Tierney et al., 2021).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Tierney et al., 2021 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAstrocyte immune activation has downstream impacts on cellular glutamate uptake and calcium signaling.
“Previous work has also highlighted the downstream impacts of astrocyte immune activation on cellular glutamate uptake and calcium signaling (Agulhon et al., 2012; Haroon et al., 2017; Shigetom, et al., 2019; Vallejo-Illarramendi et al., 2006).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites Agulhon et al., 2012 source
The section on activated microglia and reactive astrocytes describes inflammatory mediators producing astrocytic Ca2+ elevations and glutamate release; the Summary and Perspectives likewise links reactive astrocytes to Ca2+-dependent glutamate release. These passages support the calcium-signaling part, but concern glutamate release, not an effect of immune activation on cellular glutamate uptake. No page number is provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Haroon et al., 2017 source
- cites Shigetom, et al., 2019
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationDisruption of cholesterol homeostasis perturbs cell-autonomous and non-cell-autonomous functions, including inhibition of crucial signaling pathways and cellular crosstalk.
“Disruption of cholesterol homeostasis has also been shown to perturb cell-autonomous and non-cell-autonomous functions, including inhibition of crucial signaling pathways and cellular crosstalk (Bjorkhem and Meaney, 2004; Martin et al., 2014).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLipid droplet accumulation and upregulation of key transcripts also occur in reactive astrocytes.
“Historically, astrocyte activation has been characterized by cellular hypertrophy and an increase in glial fibrillary acidic protein (GFAP) expression; however, recent work has shown that lipid droplet accumulation and the upregulation of key transcripts also occur in reactive astrocytes (Pekny and Nilsson, 2005; Sofroniew, 2009).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Pekny and Nilsson, 2005 source
- cites Sofroniew, 2009 source
The Introduction and “Extensive molecular repertoire of reactive astrocytes” sections describe changes in molecular expression as astrocytes become reactive, supporting the transcript-expression part in broad terms. Our copy does not report lipid droplet accumulation in reactive astrocytes (searched for lipid droplets and lipid accumulation). (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationDhcr7Δ3-5/T93M mice are heterozygous for a Dhcr7 targeting vector containing a neomycin insertion that deletes Dhcr7 exons III, IV and part of V, and carry a dinucleotide mutation in codon 89.
“are heterozygous for a Dhcr7 targeting vector containing a neomycin insertion, which results in deletion of Dhcr7 exons III, IV and part of V, along with a dinucleotide mutation in codon 89 (Correa-Cerro et al., 2006; Wassif et al., 2001).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Correa-Cerro et al., 2006 source
- cites Wassif et al., 2001 source
The “Disruption of the Dhcr7 gene” section describes a targeting vector that inserts a neomycin gene and deletes exons III, IV and part of V; it also reports heterozygous mice. It does not describe Dhcr7Δ3-5/T93M mice or a dinucleotide mutation at codon 89. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSLOS presents with a wide range of phenotypes including microcephaly, structural malformations, intellectual disability and behavioral issues.
“SLOS presents with a wide range of phenotypes including microcephaly, structural malformations, intellectual disability and behavioral issues (Bianconi et al., 2015; Lee et al., 2013).”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReactive astrocytes also induce adverse outcomes.
“Although the purpose of astrocyte activation is to limit tissue damage, growing evidence shows that reactive astrocytes also induce adverse outcomes (Guttenplan et al., 2021; Liddelow and Barres, 2017; Liddelow et al., 2017).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Guttenplan et al., 2021 source
- cites Liddelow and Barres, 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Liddelow et al., 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAstrocyte activation is characterized by cellular hypertrophy and increased GFAP expression.
“Historically, astrocyte activation has been characterized by cellular hypertrophy and an increase in glial fibrillary acidic protein (GFAP) expression; however, recent work has shown that lipid droplet accumulation and the upregulation of key transcripts also occur in reactive astrocytes (Pekny and Nilsson, 2005; Sofroniew, 2009).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Pekny and Nilsson, 2005 source
- cites Sofroniew, 2009 source
The 'Defining reactive astrogliosis' section describes progressive cellular hypertrophy and changes in molecular expression in reactive astrocytes. It does not identify increased GFAP expression as one of those changes, so the GFAP-specific part of the claim is not supported by the passages found in our copy. Page numbers were not available. (LLM, conf=0.83)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataPharmacological inhibition of cholesterol synthesis in control astrocytes results in cellular hypertrophy and increased GFAP intensity.
“Although pharmacological inhibition of cholesterol synthesis resulted in hallmark morphological changes observed upon astrocyte activation (Fig. 5B), including cellular hypertrophy and increased GFAP intensity (Fig. 5C,D), the expression of reactive transcripts was not consistent with our findings in Dhcr7 astrocytes (Fig. 5E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFollowing 7 days of LPDS culture, Dhcr7 astrocytes exhibit reduced cholesterol and detection of 7-DHC by GC/MS.
“Following 7 days of LPDS culture, Dhcr7 astrocytes exhibited the expected biochemical phenotype with a reduction in cholesterol and the detection of 7-DHC when analyzed by gas chromatography/mass spectrometry (GC/MS) (Fig. S1B,C).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCholesterol metabolism plays a role within the astrocyte-microglia immune axis, with possible implications in other neurological diseases.
“Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte–microglia immune axis, with possible implications in other neurological diseases.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal work was reviewed and approved by the Institutional Animal Care and Use Committee at Sanford Research (protocol #186-09-24B).
“All animal work was reviewed and approved by the Institutional Animal Care and Use Committee at Sanford Research (protocol #186-09-24B).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningOnly some reactive transcripts are changed, suggesting that a different subset of reactive astrocytes is present and is induced by a different stimulus.
“Although microglia appear to induce a reactive astrocyte state, only some reactive transcripts are changed, suggesting that a different subset of reactive astrocytes is present and is induced by a different stimulus.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationDhcr7WT/T93M mice are used as controls for experiments with Dhcr7Δ3-5/T93M mice.
“As previously reported, Dhcr7WT/T93M mice are used as controls for experiments with Dhcr7Δ3-5/T93M mice (Correa-Cerro et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Correa-Cerro et al., 2006 source
May combine two claims.
PremisereasoningSLOS results in reduced cholesterol levels accompanied by accumulation of the precursor 7-DHC.
“This results in reduced cholesterol levels, accompanied by the accumulation of the precursor 7-DHC.”
Quote in the paperSubstantial claim- Rests on an assumption: SLOS results in reduced cholesterol levels accompanied by accumulation of the precursor 7-DHC.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenCalcium imaging analysis included three biological replicates per group with at least ten cells analyzed for each replicate.
“Calcium imaging analysis included three biological replicates per group with at least ten cells being analyzed for each replicate.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAll comparisons for statistical analyses were made relative to vehicle-treated (DMSO) controls cultured in LPDS conditions.
“All comparisons for statistical analyses were made relative to vehicle-treated controls (dimethyl sulphoxide, DMSO; Thermo Fisher Scientific, BP231-100) cultured in LPDS conditions.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLittermates were used for all experiments.
“Littermates were used for all experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll research was approved by the Sanford Research Institutional Biosafety Committee (#2019101).
“All research was approved by the Sanford Research Institutional Biosafety Committee (#2019101).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCholesterol homeostasis impacts astroglia-immune connectivity and function, with implications for neurological diseases associated with cholesterol disruption, such as SLOS.
“These data suggest a previously unreported regulatory mechanism by which cholesterol homeostasis impacts astroglia–immune connectivity and function, with implications for neurological diseases associated with cholesterol disruption, such as SLOS (Fig. 8).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataReactive Dhcr7 microglia drive astrocyte activation, disturbing downstream astrocyte functionality, including glutamate responsiveness and calcium activity.
“Reactive Dhcr7 microglia then drive astrocyte activation, disturbing downstream astrocyte functionality, including glutamate responsiveness and calcium activity.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenCulturing glia in 10% lipoprotein-deficient serum for 7 days forces cells to utilize endogenous cholesterol synthesis mechanisms and prevents lipoprotein-mediated internalization from the culture medium.
“To force cells to utilize endogenous cholesterol synthesis mechanisms and prevent lipoprotein-mediated internalization from the culture medium, the medium containing FBS was removed and glia were cultured in 10% lipoprotein-deficient serum (LPDS) for 7 days.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataIdentification of trimethylsilyl ethers of natural sterols was determined through comparison to commercially available standards for cholesterol, 7-DHC, lathosterol and desmosterol, and to MS spectra in the NIST Standard Reference Database when available.
“Identification of trimethylsilyl ethers of natural sterols was determined through comparison to commercially available standards for cholesterol, 7-DHC, lathosterol and desmosterol (Avanti Polar Lipids), as well as comparison to MS spectra through the National Institute of Standards and Technologies Standard Reference Database when available.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningGlial cholesterol biosynthesis is critical for the suppression of reactive gliosis, with relevance to both disorders of cholesterol biosynthesis and neurological disease.
“These studies suggest that glial cholesterol biosynthesis is critical for the suppression of reactive gliosis, with relevance to both disorders of cholesterol biosynthesis and neurological disease.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningDhcr7 astrocytes exhibit impaired function, likely due to immune activation.
“These data suggest that Dhcr7 astrocytes exhibit impaired function, likely due to immune activation.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenLPDS preparations were lot tested to confirm cholesterol depletion and maintenance of cell viability and growth.
“LPDS preparations were lot tested to confirm cholesterol depletion and maintenance of cell viability and growth.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAstrocyte and microglia cultures were confirmed to be free of mycoplasma contaminants every 3-4 months.
“Cultures were confirmed to be free of mycoplasma contaminants every 3-4 months.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSLOS results from mutations in DHCR7, which reduces 7-dehydrocholesterol (7-DHC) to cholesterol in the final step of the cholesterol biosynthesis pathway.
“SLOS results from mutations in DHCR7, which reduces 7-dehydrocholesterol (7-DHC) to cholesterol in the final step of the cholesterol biosynthesis pathway (Smith et al., 1964).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Smith et al., 1964 source
May combine two claims.
Interpretationown dataDhcr7 disruption alters astrocyte-microglia crosstalk, likely driving pathological phenotypes that can affect neuronal function and overall brain health.
“Our data suggest that Dhcr7 disruption alters astrocyte–microglia crosstalk, likely driving pathological phenotypes that can affect neuronal function and overall brain health.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Astrocytes and their associated cellular impacts within SLOS have received less attention.
“Although the impact of DHCR7 disruption on neuronal dysfunction has been extensively studied, astrocytes and their associated cellular impacts within SLOS have received less attention.”
The paper relies on this without support.
Cholesterol homeostasis is critical for normal brain development and function.
“Maintenance of cholesterol levels in the brain, the most cholesterol-rich organ in the body, is critical for normal development and function.”
The paper relies on this without support.
SLOS results in reduced cholesterol levels accompanied by accumulation of the precursor 7-DHC.
“This results in reduced cholesterol levels, accompanied by the accumulation of the precursor 7-DHC.”
The paper relies on this without support.
Limited work has analyzed endogenous microglia lipid metabolism to ascertain its importance.
“Although microglia typically become reactive in response to neuronal damage or loss, limited work has analyzed endogenous microglia lipid metabolism to ascertain its importance.”
The authors state this as an assumption.
The compared groups have equal variance, so that unpaired two-tailed t-tests, one-way ANOVA and Dunnett's post hoc tests are valid.
“Assuming equal variance, data were analyzed by unpaired two-tailed t-test or one-way ANOVA and post hoc Dunnett's t-test for multiple comparisons relative to LPDS control groups.”
The paper relies on this without support.
AY9944 inhibits DHCR7, U18666A inhibits DHCR24, and atorvastatin inhibits HMG-CoA reductase, so that these compounds disrupt cholesterol synthesis at those specific steps.
“AY9944 (5 µM; DHCR7 inhibitor; Cayman Chemical, 14611), U18666A (20 nM; DHCR24 inhibitor; Cayman Chemical, 10009085) and atorvastatin (2.5 µM; HMG-CoA reductase inhibitor; Cayman Chemical, 10493).”
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.
Thr-to-Met change is called silent
MinorThe text describes an ACA (Thr) to ATG (Met) amino-acid substitution, then calls that change a silent polymorphism. A substitution that changes the encoded amino acid is not silent.
“resulting in an ACA (Thr) to ATG (Met) change”
“This is a silent polymorphism that recapitulates a common point mutation occurring in SLOS patients.”
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“…activation, aberrant calcium signaling, disturbed glutamate uptake, downstream impacts on neurite outgrowth and synaptogenesis, and APOE secretion (Dong et al., 2018; Higashimori et al., 2016; Jacobs and Doering, 2010; Laurence and Fatemi, 2005; Trachtenberg et al., 2012; Vargas et al., 2005).”
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“Previous work has also highlighted the downstream impacts of astrocyte immune activation on cellular glutamate uptake and calcium signaling (Agulhon et al., 2012; Haroon et al., 2017; Shigetom, et al., 2019; Vallejo-Illarramendi et al., 2006).”
Butchbach, M. E. R., Tian, G., Guo, H., & Lin, C. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403938200 · Cited by 166 · see citing works
Wassif, C. A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.6.555 · Cited by 164 · see citing works
Abnormalities of cholesterol metabolism in autism spectrum disorders
Tierney, E., Bukelis, I., Thompson, R. E., Ahmed, K., Aneja, A., Kratz, L., & Kelley, R. I. (2006) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30368 · Cited by 163 · cited 10× · see citing works
“This results in reduced cholesterol levels, accompanied by the accumulation of the precursor 7-DHC. SLOS presents with a wide range of phenotypes including microcephaly, structural malformations, intellectual disability and behavioral issues (Bianconi et al., 2015; Lee et al., 2013).”
InfluentialCa2+ sources for the exocytotic release of glutamate from astrocytes
Parpura, V., Grubišić, V., & Verkhratsky, A. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.11.006 · Cited by 159 · cited 2× · see citing works
“Gliotransmitters have been shown to act on neurons and vascular smooth muscles to regulate synapse release and blood flow (Bazargani and Attwell, 2016; Parpura et al., 2011).”
SnapShot: Astrocytes in Health and Disease
Liddelow, S. A., & Barres, B. A. (2015) · Cell · doi:10.1016/j.cell.2015.08.029 · Cited by 148 · see citing works
Increased expression and function of glutamate transporters in multiple sclerosis
Vallejo‐Illarramendi, A., Domercq, M., Pérez‐Cerdá, F., Ravid, R., & Matute, C. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.06.017 · Cited by 146 · see citing works
Korade, Ž., Xu, L., Shelton, R. C., & Porter, N. A. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m009365 · Cited by 145 · cited 1× · see citing works
“Various structural and functional deficits resulting from Dhcr7 disruption have been previously described in neurons and neural progenitors using these animals and cellular models (Francis et al., 2016; Jiang et al., 2010; Korade et al., 2010; Xu et al., 2013).”
Andjelkovic, A. V., Nikolic, B., Pachter, J. S., & Zečević, N. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00830-0 · Cited by 139 · cited 1× · see citing works
“As the resident immune cells of the brain, microglia function in the surveillance of the brain milieu to respond to injury or disease (Andjelkovic et al., 1998; Li and Barres, 2018).”
The effects of APOE on the functional architecture of the resting brain
Trachtenberg, A. J., Filippini, N., Ebmeier, K. P., Smith, S. M., Karpe, F., & Mackay, C. E. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.07.059 · Cited by 129 · cited 1× · see citing works
“…activation, aberrant calcium signaling, disturbed glutamate uptake, downstream impacts on neurite outgrowth and synaptogenesis, and APOE secretion (Dong et al., 2018; Higashimori et al., 2016; Jacobs and Doering, 2010; Laurence and Fatemi, 2005; Trachtenberg et al., 2012; Vargas et al., 2005).”
Lundin, A., Delsing, L., Clausen, M., Ricchiuto, P., Sánchez, J., Sabirsh, A., Ding, M., Synnergren, J., Zetterberg, H., Brolén, G., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.01.021 · Cited by 128 · see citing works
Cholesterol Biosynthesis and Uptake in Developing Neurons
Genaro-Mattos, T. C., Anderson, A., Allen, L. B., Korade, Z., & Mirnics, K. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00248 · Cited by 117 · see citing works
Higashimori, H., Schin, C. S., Chiang, M. S. R., Morel, L., Shoneye, T. A., Nelson, D. L., & Yang, Y. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1069-16.2016 · Cited by 105 · cited 1× · see citing works
“…activation, aberrant calcium signaling, disturbed glutamate uptake, downstream impacts on neurite outgrowth and synaptogenesis, and APOE secretion (Dong et al., 2018; Higashimori et al., 2016; Jacobs and Doering, 2010; Laurence and Fatemi, 2005; Trachtenberg et al., 2012; Vargas et al., 2005).”
Pathogenesis, epidemiology, diagnosis and clinical aspects of smith-lemli-opitz syndrome
Bianconi, S. E., Cross, J. L., Wassif, C. A., & Porter, F. D. (2015) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2015.1014472 · Cited by 84 · cited 1× · see citing works
“This results in reduced cholesterol levels, accompanied by the accumulation of the precursor 7-DHC. SLOS presents with a wide range of phenotypes including microcephaly, structural malformations, intellectual disability and behavioral issues (Bianconi et al., 2015; Lee et al., 2013).”
Das, S., Li, Z., Noori, A., Hyman, B. T., & Serrano-Pozo, A. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01898-y · Cited by 80 · see citing works
Francis, K. R., Ton, A. N., Xin, Y., O'Halloran, P. E., Wassif, C. A., Malik, N., Williams, I. M., Cluzeau, C. V. M., Trivedi, N. S., Pavan, W. J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4067 · Cited by 79 · cited 1× · see citing works
“Various structural and functional deficits resulting from Dhcr7 disruption have been previously described in neurons and neural progenitors using these animals and cellular models (Francis et al., 2016; Jiang et al., 2010; Korade et al., 2010; Xu et al., 2013).”
Self-citationCorrea-Cerro, L. S., Wassif, C. A., Kratz, L., Miller, G. F., Munasinghe, J. P., Grinberg, A., Fliesler, S. J., & Porter, F. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl003 · Cited by 75 · see citing works
Parviainen, L., Dihanich, S., Anderson, G. W., Wong, A. M. S., Brooks, H., Abeti, R., Rezaie, P., Lalli, G., Pope, S. A. S., Heales, S., et al. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0476-y · Cited by 72 · cited 1× · see citing works
“Mouse astrocytes and microglia were purified from P2-P5 cerebral cortices and cultured as previously described (Parviainen et al., 2017).”
Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?
Yang, L., Zhou, Y., Jia, H., Qi, Y., Tu, S., & Shao, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01818 · Cited by 64 · see citing works
Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells
Xu, L., Korade, Ž., Rosado, D. A., Mirnics, K., & Porter, N. A. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m035733 · Cited by 59 · cited 1× · see citing works
“Various structural and functional deficits resulting from Dhcr7 disruption have been previously described in neurons and neural progenitors using these animals and cellular models (Francis et al., 2016; Jiang et al., 2010; Korade et al., 2010; Xu et al., 2013).”
Anderson, R. H., Sochacki, K. A., Vuppula, H., Scott, B. L., Bailey, E. M., Schultz, M. M., Kerkvliet, J. G., Taraska, J. W., Hoppe, A. D., & Francis, K. R. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110008 · Cited by 59 · see citing works
Self-citationSimvastatin alters M1/M2 polarization of murine BV2 microglia via Notch signaling
Wu, F., Luo, T., Yuanwu, M., Liu, H., Dong, J., Fang, Y., Peng, J., & Guo, Y.-J. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.12.010 · Cited by 55 · see citing works
Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome
Lee, R. W. Y., Conley, S. K., Gropman, A., Porter, F. D., & Baker, E. H. (2013) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.36096 · Cited by 54 · cited 1× · see citing works
“This results in reduced cholesterol levels, accompanied by the accumulation of the precursor 7-DHC. SLOS presents with a wide range of phenotypes including microcephaly, structural malformations, intellectual disability and behavioral issues (Bianconi et al., 2015; Lee et al., 2013).”
McFarland, A. J., Davey, A. K., & Anoopkumar‐Dukie, S. (2017) · Mediators of Inflammation · doi:10.1155/2017/2582745 · Cited by 46 · cited 1× · see citing works
“…through attenuated lipopolysaccharide-induced cytokine release, suppressed reactive oxygen species generation, and increased M2/M1 macrophage ratio (McFarland et al., 2017; Xu et al., 2017), possibly through suppression of toll-like receptor (TLR) and/or Notch signaling pathways (Han et al., 2018;…”
Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes
Dong, Q., Liu, Q., Li, R., Wang, A., Bu, Q., Wang, K. H., & Chang, Q. (2018) · eLife · doi:10.7554/elife.33417 · Cited by 42 · cited 2× · see citing works
“…activation, aberrant calcium signaling, disturbed glutamate uptake, downstream impacts on neurite outgrowth and synaptogenesis, and APOE secretion (Dong et al., 2018; Higashimori et al., 2016; Jacobs and Doering, 2010; Laurence and Fatemi, 2005; Trachtenberg et al., 2012; Vargas et al., 2005).”
Jiang, X.-S., Wassif, C. A., Backlund, P. S., Li, S., Holtzclaw, L. A., Li, Z., Yergey, A. L., & Porter, F. D. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq011 · Cited by 41 · cited 1× · see citing works
“Various structural and functional deficits resulting from Dhcr7 disruption have been previously described in neurons and neural progenitors using these animals and cellular models (Francis et al., 2016; Jiang et al., 2010; Korade et al., 2010; Xu et al., 2013).”
Sterols in the central nervous system
Mulder, M. T. (2009) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32832182da · Cited by 37 · cited 1× · see citing works
“…identified a direct impairment of neurite outgrowth and synapse formation when cholesterol biosynthesis was disrupted in astrocytes alone, further highlighting the importance of astrocyte health and function in the context of neurodevelopmental disorders (Mulder, 2009; Pfrieger and Ungerer, 2011).”
Singh, S. K., Kordula, T., & Spiegel, S. (2021) · Glia · doi:10.1002/glia.24135 · Cited by 36 · cited 1× · see citing works
“Human astrocytes were used so that human-specific primers corresponding to reactive astrocyte transcripts (Table S3) could be designed (Singh et al., 2022).”
Endo‐Umeda, K., Yasuda, K., Sugita, K., Honda, A., Ohta, M., Ishikawa, M., Hashimoto, Y., Sakaki, T., & Makishima, M. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.11.010 · Cited by 27 · see citing works
Tierney, E., Remaley, A. T., Thurm, A., Jager, L. R., Wassif, C. A., Kratz, L. E., Bailey-Wilson, J. E., Bukelis, I., Sarphare, G., Jung, E. S., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01580-8 · Cited by 26 · cited 1× · see citing works
“Additionally, loss of cholesterol homeostasis has been implicated in numerous neurological disorders, including autism spectrum disorder (Tierney et al., 2021).”
Han, J. Z., Yin, Q., Yang, F., Shou, W., Zhang, C., & Guo, F. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9055 · Cited by 8 · cited 1× · see citing works
“…lipopolysaccharide-induced cytokine release, suppressed reactive oxygen species generation, and increased M2/M1 macrophage ratio (McFarland et al., 2017; Xu et al., 2017), possibly through suppression of toll-like receptor (TLR) and/or Notch signaling pathways (Han et al., 2018; Wu et al., 2018).”
Kanuri, B., Fong, V., Ponny, S. R., Tallman, K. A., Rao, S. R., Porter, N. A., Fliesler, S. J., & Patel, S. B. (2020) · Journal of Lipid Research · doi:10.1194/jlr.ra120001101 · Cited by 5 · cited 1× · see citing works
“A recently developed mouse carrying LoxP-flanked Dhcr7 should enable the discernment of cell-type-specific impacts of Dhcr7 deletion (Kanuri et al., 2020).”
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Function and therapeutic value of astrocytes in diabetic cognitive impairment
Meng, F., Fu, J., Zhang, L., Guo, M., Zhuang, P., Yin, Q., & Zhang, Y. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105591 · Cited by 25 · see citing works
Sterol pathway disruption in pregnancy: a link to autism
Peeples, E. S., Anzalone, A. J., Dai, R., Reisher, E., Korade, Ž., & Mirnics, K. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03610-7 · Cited by 5 · see citing works
“Notably, 7-DHC is the most oxidizable lipid [17 – 20] and gives rise to the formation of reactive autoxidation sterols which disrupt cell viability, differentiation, growth [21 – 25], and potentially vitamin D metabolism [26].”
Dishevelled localization and function are differentially regulated by structurally distinct sterols
Sengupta, S., Yaeger, J. D. W., Schultz, M. M., May, D. G., Roux, K. J., & Francis, K. R. (2025) · iScience · doi:10.1016/j.isci.2025.112704 · Cited by 6 · see citing works
“These heterozygous mice carry deletions of Dhcr7 exons III, IV and part of V, and a dinucleotide mutation in codon 89 56,57 As reported previously, 55,56 Dhcr7 WT/T93M mice were used as experimental controls for Dhcr7 Δ 3-5/T93M mice.”
Self-citationŻukowska, A., Król, M., Kupnicka, P., Bąk, K., Janawa, K., & Chlubek, D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146672 · Cited by 4 · see citing works
“The study demonstrated that cholesterol homeostasis is essential for normal astrocyte and microglial function, and its disruption contributes to neurological abnormalities seen in SLOS [106] and Alzheimer’s disease [107].”
Dishevelled localization and function are differentially regulated by structurally distinct sterolsPreprint
Sengupta, S., Yaeger, J. D. W., Schultz, M. M., & Francis, K. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.14.593701 · Cited by 4 · see citing works
Self-citationKawatani, K., Baker, S. K., Yaeger, J. D. W., Anderson, R. H., Ren, Y., Li, Z., Bao, H., Han, X., Francis, K. R., & Kanekiyo, T. (2025) · Human Molecular Genetics · doi:10.1093/hmg/ddaf159 · Cited by 3 · see citing works
“Previous work has demonstrated that primary astrocytes from Dhcr7 − / − mice exhibit heightened immune signaling, dysregulation of glutamate and calcium signaling, and altered microglial crosstalk [36].”
Self-citationPost-lanosterol inhibition profile based classification of commonly used prescription medications
Tallman, K. A., Anderson, A. C., Mirnics, K., Porter, N. A., & Korade, Ž. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03785-7 · Cited by 3 · see citing works
“These oxysterols are toxic and signi fi cantly impair cell viability and growth [12 – 16].”
Hydroxyzine Effects on Post-Lanosterol Biosynthesis in Smith–Lemli–Opitz Syndrome (SLOS) Models
Korade, Ž., Anderson, A. C., Balog, M., Tallman, K. A., Porter, N. A., & Mirnics, K. (2025) · Biomolecules · doi:10.3390/biom15040562 · Cited by 3 · see citing works
Optics-free spatial genomics for mapping mammalian brain aging by IRISeq
Abdulraouf, A., Jiang, W., Zhang, Z., Xu, Z., Lu, Z., Merlinsky, T. R., Liao, A., Doymaz, A., Isakov, S., Raihan, T., et al. (2026) · Nature Neuroscience · doi:10.1038/s41593-026-02293-1 · Cited by 15 · see citing works
“Although this state has not been reported previously, prior studies have shown that Dhcr7 is expressed in a subset of microglia, with its deficiency driving increased microglial activation and astrocyte reactivity 47 .”
Elevated Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels in Smith-Lemli-Opitz Syndrome
Luke, R., Cawley, N. X., Rahhal, S. N., Selvaraman, A., Thurm, A. E., Wassif, C. A., & Porter, F. D. (2024) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2024.108570 · Cited by 2 · see citing works
Macrophage signaling and function are regulated by distinct sterol biochemistries
Yaeger, J. D. W., Pradhan, B., Kerkvliet, J. G., Lawver, A. G., Sengupta, S., Thiex, N. W., & Francis, K. R. (2026) · Journal of Lipid Research · doi:10.1016/j.jlr.2026.101054 · Cited by 1 · see citing works
Self-citationSterol biosynthesis, brain development, and disease
Peeples, E. S., Korade, Ž., & Mirnics, K. (2026) · Journal of Clinical Investigation · doi:10.1172/jci208000 · Cited by 1 · see citing works
“These changes were driven by microglial signaling (51).”
Malin, K., Conley, A. J., Verstraete, M., Norris, J. K., Hsu, Y.-C., Holl, W., van Heule, M., Vieira, F., Scoggin, K. E. S., Ball, B. A., et al. (2026) · Endocrinology · doi:10.1210/endocr/bqag083 · Cited by 1 · see citing works
Altered Cerebrospinal Fluid Proteins in Smith–Lemli–Opitz Syndrome
Li, W., Pergande, M. R., Serna‐Perez, F., Patel, V., Crutchfield, C. A., Searle, B. C., Picache, J. A., Farhat, N. M., Wassif, C. A., Backlund, P. S., et al. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00282
Self-citationSui, X., Han, D. J., Costa, D. M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.07.723652
Vellingiri, B., Kinoshita, M., Elangovan, A., Dahiya, B., Kumar, N., Uvarajan, D., Ohara, H., Durairajan, S. S. K., Siama, Z., Narayanasamy, A., et al. (2026) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2026.107087
Cholesterol deficiency in Smith-Lemli-Opitz syndrome: clinical and pharmaceutical relevance
Mendes, F. (2026) · Athena health & research journal. · doi:10.62741/ahrj.v3isuppl.2.162
- Authors
- Freel, B. A., Kelvington, B. A., Sengupta, S., Mukherjee, M., & Francis, K. R.
- Affiliations
- University of South Dakota (US)
- Sanford Research (US)
- Venue
- Disease Models & Mechanisms
- Publisher
- The Company of Biologists
- Published
- 2022-12-01
- Volume
- 15
- Issue
- 12
- ISSN
- 1754-8403 (ISSN-L)
- 1754-8411
- PMC
- PMC10655813
- OpenAlex
- W4311894659
- Cited by
- 17
- References
- 79
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 2 · 2023: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Disease Models & Mechanisms (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (P20 GM103620, P20 GM103548)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R25HD097633)
- National Science Foundation (DGE-1633213)
- Smith-Lemli-Opitz/RSH Foundation
- Sanford Research
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Smith-Lemli-Opitz syndrome, DHCR7, cholesterol biosynthesis, astrocyte-microglia crosstalk, microglia, glial fibrillary acidic protein, calcium signaling, cholesterol homeostasis, brain development, neurological deficit
- MeSH terms
- Animals, Cholesterol, Phenotype, Sterols, Microglia, Smith-Lemli-Opitz Syndrome, Mice
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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