Excess protein synthesis in FXS patient lymphoblastoid cells can be rescued with a p110β-selective inhibitor.
ABSTRACT The fragile X mental retardation protein (FMRP) plays a key role for neurotransmitter-mediated signaling upstream of neuronal protein synthesis. Functional loss of FMRP causes the inherited intellectual disability fragile X syndrome (FXS), and leads to increased and stimulus-insensitive neuronal protein synthesis in FXS animal models. Previous studies suggested that excess protein synthesis mediated by dysregulated signal transduction contributes to the majority of neurological defects in FXS, and might be a promising target for therapeutic strategies in patients. However, possible impairments in receptor-dependent protein synthesis have not been evaluated in patient cells so far. Using quantitative fluorescent metabolic labeling, we demonstrate that protein synthesis is exaggerated and cannot be further increased by cytokine stimulation in human fragile X lymphoblastoid cells. Our previous work suggested that loss of FMRP-mediated regulation of protein expression and enzymatic function of the PI3K catalytic subunit p110β contributes to dysregulated protein synthesis in a mouse model of FXS. Here, we demonstrate that these molecular mechanisms are recapitulated in FXS patient cells. Furthermore, we show that treatment with a p110β-selective antagonist rescues excess protein synthesis in synaptoneurosomes from an FXS mouse model and in patient cells. Our work suggests that dys-regulated protein synthesis and PI3K activity in patient cells might be suitable biomarkers to quantify the efficacy of drugs to ameliorate molecular mechanisms underlying FXS, and could be used for drug screens to refine treatment strategies for individual patients. Moreover, we provide rationale to pursue p110β-targeting treatments as potential therapy in FXS, and possibly other autism spectrum disorders.
Full-textDOI: · Available from: Gary Bassell, May 24, 2015
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Article: Excess protein synthesis in FXS patient lymphoblastoid cells can be rescued with a p110β-selective inhibitor.
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ABSTRACT: Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.Frontiers in Cellular Neuroscience 02/2015; 9:55. DOI:10.3389/fncel.2015.00055 · 4.18 Impact Factor
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ABSTRACT: The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) 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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.060 · 7.21 Impact Factor
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ABSTRACT: 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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.065 · 7.21 Impact Factor