Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Groß, Christina; Bassell, Gary J.

doi:10.2119/molmed.2011.00363

Cited by 65 publications

(74 citation statements)

References 36 publications

(63 reference statements)

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“…We have previously shown that activity of the PI3K catalytic subunit p110β is increased in the absence of FMRP (Gross and Bassell, 2012; Gross et al, 2010). Here, we show that Centg1 heterozygosity reduced p110β-associated PI3K activity in Fmr1 KO cortical synaptic fractions to wild type levels (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome

et al. 2015

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Summary The PI3K enhancer PIKE links PI3K catalytic subunits to metabotropic glutamate receptors (mGlu) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability Fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity, and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.

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Section: Resultsmentioning

confidence: 99%

Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome

et al. 2015

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“…Absence of FMRP in the mouse model and in patient cells leads to increased and stimulus-insensitive protein synthesis (Gross et al, 2010; Gross and Bassell, 2012; Kumari et al, 2014; Osterweil et al, 2010; Weiler et al, 2004), which is believed to contribute to neuronal dysfunction and impaired cognition in FXS. Here, we show that genetically reducing p110β decreases elevated basal protein synthesis rates (Figure 4A) and restores mGlu1/5-mediated stimulation of protein synthesis rates in Fmr1 KO cortical synaptic fractions (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…PI3K activity was measured with a PI3-Kinase Activity ELISA: Pico ( Echelon Biosciences, Inc. ) according to the manufacturer’s protocol as described previously (Gross and Bassell, 2012). PIP2 and PIP3 in the hippocampus were quantified using PI(3,4,5)P 3 and PI(4,5)P 2 mass ELISA kits ( Echelon Biosciences, Inc. ) , following the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…One of those, Pik3cb mRNA, which encodes the PI3K catalytic subunit p110β, has been confirmed as FMRP-associated mRNA in three independent studies (Ascano et al, 2012; Gross et al, 2010; Miyashiro et al, 2003). Increased expression of p110β protein was observed in the brains of Fmr1 knockout ( Fmr1 KO ) mice (Gross et al, 2010; Sharma et al, 2010) and in FXS patient cells (Gross and Bassell, 2012; Kumari et al, 2014). Here, we employed genetic rescue strategies in FXS mouse models to test the hypothesis that increased p110β protein contributes to FXS-associated molecular, behavioral and cognitive defects, and thus may be a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

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Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome

et al. 2015

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Summary Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the Fragile X Mental Retardation Protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition.

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“…In studies using rabbit reticulocyte lysate assays it was shown that FMRP caused a dose-dependent inhibition of the translation of brain poly(A) RNA 39,40 and translation was increased in cortical synaptoneurosome preparations from Fmr1 knockout mice as assayed by 35 S-methionine labeling 41,42 . These in vitro studies are supported by several types of protein synthesis assays in cell cultures from FXS patients and brain slices from Fmr1 knockout mice 41,43,44 .…”

Section: A Role For a General Translational Increase In Fragile X Synmentioning

confidence: 99%

The translation of translational control by FMRP: therapeutic targets for FXS

2013

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Summary De novo protein synthesis is necessary for long-lasting modifications in synaptic strength and dendritic spine dynamics that underlie cognition1. Fragile X syndrome, characterized by intellectual disability and autistic behaviors, holds promise for revealing the molecular basis for these long-term changes in neuronal function. Loss-of-function of FMRP, the fragile X mental retardation protein, results in defects in synaptic plasticity and cognition in many models of the disease. FMRP is a polyribosome-associated RNA binding protein that regulates the synthesis of a set of plasticity-related proteins by stalling ribosomal translocation on target mRNAs. The recent identification of mRNA targets of FMRP and its upstream regulators, and the use of small molecules to stall ribosomes in the absence of FMRP, have the potential to be translated into novel therapeutic avenues for the treatment of FXS.

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Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Cited by 65 publications

References 36 publications

Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome

Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome

Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome

The translation of translational control by FMRP: therapeutic targets for FXS

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