Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome
Open accessAbstract
Fragile X syndrome (FXS) is an inherited neurologic disease caused by loss of fragile X mental retardation protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knock-out neurons, excess synaptic PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in FMRP-deficient non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110β, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110β translation, p110β protein expression, and PI3K activity. In contrast, both p110β protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knock-out. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS-associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization, and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS.
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The mTor pathway alteration in Fmr1-knockout neurons is not due to altered expression of mTor but rather to overactivation of PI3K because of overexpression of the catalytic PI3K subunit p110β.
“This alteration is not due to an altered expression of mTor (Sharma et al., 2010), but rather to the overactivation of PI3K, because of the overexpression of the catalytic PI3K subunit p110β (Gross et al., 2010; Gross and Bassell, 2012).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Gross et al., 2010
The Results report increased PI3K activity and increased synaptic p110β protein in Fmr1-knockout neurons. They say excess p110β could contribute to the abnormal PI3K activity, but do not establish it as the definitive cause implied by “because of.” The mTOR-expression clause is cited to Sharma et al., not to this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPI3K is regulated by FMRP, is elevated in FXS mouse knockouts, and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.
“PI3K, which is regulated by FMRP,59 is elevated in FXS mouse knockouts,62,63 and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [62]
Pharmacological mGluR5 antagonists rescue protein synthesis and many classic outcome measures in mouse and fly FXS models.
“have demonstrated that dampening mGluR5 signalling rescues protein synthesis and many of the classic outcome measures (TABLE 1) used in the mouse and fly models30–35.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [31]
Core FXS mouse deficits, including protein synthesis, dendritic spine density and morphology, long-term depression, and audiogenic seizures, are consistently rescued by more than ten genetic approaches and multiple drug classes.
“One striking conclusion of the broad array of preclinical studies is that these core deficits can be consistently rescued by more than ten genetic approaches and multiple classes of pharmacological compounds including mGluR antagonists (MPEP, fenobam, mavoglurant and CTEP), GABA agonists, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), mechanistic target of rapamycin (mTOR) inhib”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [31]
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“This alteration is not due to an altered expression of mTor (Sharma et al., 2010), but rather to the overactivation of PI3K, because of the overexpression of the catalytic PI3K subunit p110 β (Gross et al., 2010; Gross and Bassell, 2012).”
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The neurochemical basis for the treatment of autism spectrum disorders and Fragile X syndrome
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- Authors
- Gross, C., Nakamoto, M., Yao, X., Chan, C.-B., Yim, S. Y., Ye, K., Warren, S. T., & Bassell, G. J.
- Affiliations
- Emory University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-08-11
- Volume
- 30
- Issue
- 32
- Pages
- 10624-10638
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2924772
- OpenAlex
- W2014255722
- Cited by
- 241
- References
- 56
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 19 · 2020: 15 · 2019: 8 · 2018: 11 · 2017: 21 · 2016: 24 · 2015: 22 · 2014: 26 · 2013: 13 · 2012: 27
- FWCI
- 12.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Fragile X Foundation
- National Institutes of Health
- National Institute of Mental Health (R01MH085617, MH085617)
- National Institute on Drug Abuse (R21DA027080)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD001799, HD020521, R01HD020521, P30HD024064, R37HD020521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- fragile X syndrome, FMRP, phosphatidylinositol 3-kinase, p110β, group I metabotropic glutamate receptors, synaptic protein synthesis, AMPA receptor internalization, dendritic spine density, therapeutic target, mRNA translation regulation
- MeSH terms
- Red Fluorescent Protein, Analysis of Variance, Animals, Cells, Cultured, Dendrites, Disease Models, Animal, Embryo, Mammalian, Enzyme Inhibitors, Fragile X Syndrome, Hippocampus, Humans, Luminescent Proteins, Methoxyhydroxyphenylglycol, Models, Biological, Neurons, RNA, Messenger, Synapses, Synaptosomes, Transfection, Gene Expression Regulation, Enzymologic, Receptors, AMPA, Mice, Knockout, Excitatory Amino Acid Antagonists, Phosphatidylinositol 3-Kinases, Protein Subunits, Immunoprecipitation, Green Fluorescent Proteins, Mice, Fragile X Messenger Ribonucleoprotein 1, Class I Phosphatidylinositol 3-Kinases
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