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Cited by 18Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchDown syndrome and intellectual disability research

Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome.

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Ren, Baiyan, Burkovetskaya, Maria, Jung, Yoosun, Bergdolt, Lara, Totusek, Steven, Martinez‐Cerdeno, Veronica, Stauch, Kelly, Korade, Zeljka +1 more·2023·Glia
DOI 10.1002/glia.24331PMC PMC10023374
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Abstract

Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human‐based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human‐based FXS model via differentiation of astrocytes from human‐induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca 2+signaling, impaired sterol biosynthesis, and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.

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  • Species-specific differences and differences in experimental approaches such as glutamate incubation time may explain different results in studies on astrocytic glutamate uptake.

    “Species specific differences and differences in experimental approaches such as glutamate incubation time may explain different results in studies on astrocytic glutamate uptake (Higashimori et al., 2016; Ren et al., 2023).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Ren et al., 2023

    The Results (page unavailable) contrast impaired glutamate uptake reported in mouse Fmr1-knockout astrocytes with no observed difference between human FXS and control astrocytes; the Discussion notes substantial human–rodent astrocyte differences. Experimental Procedures (page unavailable) specify a three-hour glutamate incubation, but the paper does not say that incubation time explains the differing findings. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In human FMR1 KO differentiating astrocytes, cyclin D1 is increased 2-fold, associating with reduced S phase duration in an otherwise unchanged cell cycle duration.

    “Studying human FMR1 KO differentiating astrocyte cell cycle dynamics, Ren et al. (2023) observed 2-fold increased cyclin D1 associating with reduced S phase duration in an otherwise unchanged cell cycle duration.”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Ren et al., 2023

    The Results section (‘Altered cell cycle dynamics in FXS astrocytes’; page unavailable) reports a two-fold increase in cyclin D1, a shorter estimated S phase, and no significant change in total cell-cycle duration in immature human FXS hiPSC-derived astrocytes. The paper distinguishes these patient-derived cells from its FMR1-KO hESC-derived astrocytes; the cited results are not reported for the latter, so the claim's ‘FMR1 KO’ designation is imprecise. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Proteomics analysis revealed immature signals in differentiating human iPSC-derived FMR1 KO astrocytes compared with controls.

    “The proteomics analysis revealed immature signals in differentiating human iPSC-derived FMR1 KO astrocytes when compared with controls (Ren et al., 2023).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Ren et al., 2023

    In Results (‘Altered proteome of FXS human astrocytes’), proteomic analysis found that stem-cell-derived astrocytes resembled fetal more than mature astrocytes, but that comparison was based on proteins in the control group, not an immature signature specific to FXS cells versus controls. Results (‘Differentiation of astrocytes from hiPSCs and hESCs’) identifies the FMR1-KO cells as hESC-derived; the hiPSC-derived cells were patient-derived FXS cells. The paper therefore supports a fetal-like proteomic profile, but not the claimed comparison in FMR1-KO iPSC-derived astrocytes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Ca2+ signals in response to extracellular ATP in human FMR1 KO astrocytes have increased amplitude but neither the proportion of cells responding nor the duration of the response change.

    “Ca2+ signals in response to extracellular adenosine triphosphate (ATP) in human FMR1 KO astrocytes have increased amplitude but neither the proportion of cells responding nor the duration of the response change (Ren et al., 2023).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Ren et al., 2023

    The Results section, “Altered Ca2+ signaling in FXS-astrocytes” (page unavailable), reports increased ATP-response peak amplitude with no change in the proportion responding or response duration. Those measurements were made in patient-derived FXS hiPSC-astrocytes, not the separately described FMR1-KO hESC-derived astrocytes, so the claim's cell-type designation is not supported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Astrocyte-dependent cholesterol dysregulation is implicated in several neurological disorders, including Fragile X syndrome, Alzheimer's disease and Huntington's disease.

    “Our findings are consistent with growing evidence implicating astrocyte-dependent cholesterol dysregulation in several neurological disorders, including Fragile X syndrome, Alzheimer's disease and Huntington's disease (Ren et al., 2023;Valenza et al., 2010).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Ren et al., 2023

    The Discussion reports dysregulated cholesterol biosynthesis in astrocytes derived from human Fragile X syndrome stem cells, supporting that example. The citations are grouped at the end of the sentence, and Ren et al. does not address the Alzheimer's or Huntington's disease examples in the passages found. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Ren, B., Burkovetskaya, M., Jung, Y., Bergdolt, L., Totusek, S., Martinez‐Cerdeno, V., Stauch, K., Korade, Z., & Dunaevsky, A.
Affiliations
  • University of Nebraska Medical Center (US)
  • Department of Pathology and Laboratory Medicine MIND Institute, and Institute for Pediatric Regenerative Medicine at UC Davis School of Medicine, and Shriners Hospitals for Children of Northern California Sacramento California USA
  • Department of Biochemistry and Molecular Biology University of Nebraska Medical Center Omaha Nebraska USA
Corresponding author
Dunaevsky, Anna
ORCID
Venue
Glia
Publisher
Wiley
Published
2023-01-03
Volume
71
Issue
5
Pages
1176-1196
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.24331
PMC
PMC10023374
OpenAlex
W4313454708
Cited by
18
References
14
Citations by year
2026: 4 · 2025: 5 · 2024: 5 · 2023: 4
FWCI
2.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Glia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
National Institute of Neurological Disorders and Stroke (R21NS122157, R01NS109381)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
fragile X syndrome, astrocytes, FMR1 gene silencing, cholesterol metabolism, sterol biosynthesis, calcium signaling, cell cycle, proteome, intellectual disability, human induced pluripotent stem cells, human embryonic stem cells, glial dysfunction
MeSH terms
Animals, Astrocytes, Cell Cycle, Cholesterol, Fragile X Syndrome, Humans, Proteomics, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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