Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model

Christina Gross, Anwesha Banerjee, Durgesh Tiwari, Francesco Longo, Angela R. White, A. G. Allen, Lindsay M. Schroeder-Carter, Joseph C. Krzeski, Nada A. Elsayed, Rosemary Puckett, Eric Klann, Ralph A. Rivero, Shannon L. Gourley, Gary J. Bassell

Research output: Contribution to journalArticle

Abstract

Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

Original languageEnglish (US)
JournalNeuropsychopharmacology
DOIs
StateAccepted/In press - Jan 1 2018

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Fragile X Syndrome
1-Phosphatidylinositol 4-Kinase
Protein Isoforms
Fragile X Mental Retardation Protein
Brain Diseases
Phenotype
Protein Deficiency
Dendritic Spines
Inhibition (Psychology)
Interpersonal Relations
Intellectual Disability
Cognition
Signal Transduction
Proteins
Clinical Trials
Pharmacology
Messenger RNA
Brain

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model. / Gross, Christina; Banerjee, Anwesha; Tiwari, Durgesh; Longo, Francesco; White, Angela R.; Allen, A. G.; Schroeder-Carter, Lindsay M.; Krzeski, Joseph C.; Elsayed, Nada A.; Puckett, Rosemary; Klann, Eric; Rivero, Ralph A.; Gourley, Shannon L.; Bassell, Gary J.

In: Neuropsychopharmacology, 01.01.2018.

Research output: Contribution to journalArticle

Gross, C, Banerjee, A, Tiwari, D, Longo, F, White, AR, Allen, AG, Schroeder-Carter, LM, Krzeski, JC, Elsayed, NA, Puckett, R, Klann, E, Rivero, RA, Gourley, SL & Bassell, GJ 2018, 'Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model', Neuropsychopharmacology. https://doi.org/10.1038/s41386-018-0150-5
Gross, Christina ; Banerjee, Anwesha ; Tiwari, Durgesh ; Longo, Francesco ; White, Angela R. ; Allen, A. G. ; Schroeder-Carter, Lindsay M. ; Krzeski, Joseph C. ; Elsayed, Nada A. ; Puckett, Rosemary ; Klann, Eric ; Rivero, Ralph A. ; Gourley, Shannon L. ; Bassell, Gary J. / Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model. In: Neuropsychopharmacology. 2018.
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abstract = "Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.",
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