The cyclic AMP phenotype of fragile X and autism

Kelley, Daniel J.; Bhattacharyya, Anita; Lahvis, Garet P.; Yin, Jingyi; Malter, Jim; Davidson, Richard J.

doi:10.1016/j.neubiorev.2008.06.005

Cited by 47 publications

(43 citation statements)

References 208 publications

(243 reference statements)

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“…Additional consistency is also found with FXS pathology data. cAMP levels are low in FXS, and antagonizing the cAMP-dependent phosphodiesterase PDE-4 rescues several phenotypes in the fly model (14,39,40). In this context, changes in cAMP are expected if the NCS-1/Ric8a binding is prevented, because the complex has an impact on Gs activity (19).…”

Section: Discussionmentioning

confidence: 99%

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Mansilla

Chaves-Sanjuán

Campillo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The protein complex formed by the Ca 2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.fragile X syndrome | synapse regulation | NCS-1 | protein-protein interaction inhibitor | X-ray crystallography

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Section: Discussionmentioning

confidence: 99%

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Mansilla

Chaves-Sanjuán

Campillo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, broad spectrum inhibitors of ERK1/2 and PI3K showed improvement of a few phenotypes in FXS mice but, owing to expected side effects, will not be suitable for treatment in humans [62,63,152]. Other efforts have focused on selective phenotypes of FXS, such as, for example, dendritic spine morphology by targeting p21-activating kinase [156,157], or altered cyclic adenomonophosphate levels in patients with FXS by targeting phosphodiesterase-4 [158,219].…”

Section: Neurotransmitter Receptors Versus Intracellular Signaling Anmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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“…A positive correlation was found between the plasma cAMP level and hyperkinesis and serum serotonin levels in autistic patients (Hoshino et al, 1980). Also, the production of cAMP by adenylate cyclase is decreased by opioids; this effect (i.e., opioids causing reductions in the production of cAMP) is increased in autism (Panksepp, 1979;Kelley et al, 2008). Several studies document that naltrexone (an opioid antagonist that improves adenylate cyclase function) is beneficial to some aspects of autism behavior in some patients (Riddle et al, 1999;Elchaar et al, 2006), but not to all behaviors (Willemsen-Swinkels et al, 1995;Feldman et al, 1999).…”

Section: Amino Acidsmentioning

confidence: 91%

“…Since a variety of tissues contribute to plasma cAMP levels, the cAMP is not specific to brain (Ahloulay et al, 1996). Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism (Kelley et al, 2008). Signaling deficiencies of cAMP are central to FX pathophysiology (Miyashiro and Eberwine, 2004).…”

Section: Amino Acidsmentioning

confidence: 99%