Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders

Sala, Carlo; Vicidomini, Cinzia; Bigi, Ilaria; Mossa, Adele; Verpelli, Chiara

doi:10.1111/jnc.13232

Cited by 150 publications

(136 citation statements)

References 82 publications

(255 reference statements)

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“…Although syndromic ASD has been estimated to account for only 5 to 25 % of all cases of ASD (Adviento et al 2014;de la Torre-Ubieta et al 2016;Jeste and Geschwind 2014), more forms of syndromic ASD continue to be identified (Adviento et al 2014;Richards et al 2015;Roullet et al 2013;Smile et al 2013;Yu and Berry-Kravis 2014;Yuen et al 2015). In addition, syndromic and idiopathic ASD brain impairments have been reported that are similar (Adviento et al 2014;Blackmon 2015;D'Angelo et al 2015;Guilmatre et al 2014;Klusek et al 2015;Sala et al 2015).…”

Section: Does Asd Have Neurobiological Validity?mentioning

confidence: 99%

“…Adviento et al (2014) reported that ASD occurred in four RASopathies: neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Syndromic ASD has also been found with the Shankopathies, which are genetic syndromes caused largely by mutations in SHANK2, and SHANK3 genes (Guilmatre et al 2014;Leblond et al 2014;Sala et al 2015). Many genetic variants, like the mutations in SHANK2 and SHANK3, have pleiotropic effects, that is, a single mutation results in a variety of phenotypes.…”

Section: Genetic Syndromic Asd Has Been Found With Varied Brain Impaimentioning

confidence: 99%

“…Many genetic variants, like the mutations in SHANK2 and SHANK3, have pleiotropic effects, that is, a single mutation results in a variety of phenotypes. A mutation in SHANK3 has the pleiotropic effect of generating four separate diagnostic phenotypes: ASD, schizophrenia (SCZ), severe ID, and epilepsy (Guilmatre et al 2014;Leblond et al 2014;Sala et al 2015). Hommer and Swedo (2015) noted that SHANK3 mutations, and the 22q11.2 deletion syndrome, and duplications at the Williams syndrome locus (7q11.23) all pleiotropically generated both the ASD and SCZ phenotypes.…”

Section: Genetic Syndromic Asd Has Been Found With Varied Brain Impaimentioning

confidence: 99%

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ASD Validity

Waterhouse

London

Gillberg

2016

Rev J Autism Dev Disord

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ASD research is at an important crossroads. The ASD diagnosis is important for assigning a child to early behavioral intervention and explaining a child's condition. But ASD research has not provided a diagnosis-specific medical treatment, or a consistent early predictor, or a unified life course. If the ASD diagnosis also lacks biological and construct validity, a shift away from studying ASD-defined samples would be warranted. Consequently, this paper reviews recent findings for the neurobiological validity of ASD, the construct validity of ASD diagnostic criteria, and the construct validity of ASD spectrum features. The findings reviewed indicate that the ASD diagnosis lacks biological and construct validity. The paper concludes with proposals for research going forward.Keywords DSM-5 . ASD . Autism . Diagnosis . Validity . Comorbidity . HeterogeneityThe goal of the DSM-3 nosology (American Psychiatric Association 1980) was to create reliable and standard categorical psychiatric diagnoses (Robins and Guze 1970). However, in the past 30 years, clinical, genetics, and neuroscience findings have revealed that the DSM diagnoses are not biologically valid. The National Institutes of Mental Health (NIMH) responded by proposing the Research Domain Criteria (RDoC) framework for a brain-based transdiagnostic psychiatric symptom nosology (Cuthbert and Insel 2013;Insel et al. 2010;Lilienfeld and Treadway 2016). Peterson (2015) and Weinberger et al. (2015) argued that the RDoC could not replace the DSM-5 psychiatric nosology (American Psychiatric Association 2013) or the parallel International Classification of Diseases (ICD) psychiatric nosology (World Health Organization 2012). But BFor the foreseeable future, RDoC is not envisioned as a system of psychiatric classification in its own right. Instead, in the near term, RDoC and DSM-ICD are expected to coexist. Nevertheless, RDoC is intended to provide scaffolding for a large-scale research program that will ultimately yield an alternative to DSM-ICD^ (Lilienfeld and Treadway 2016, p. 445).RDoC advocates accept that DSM-5/ICD psychiatric categories remain necessary in clinical practice, but argue that researchers should shift to RDoC study designs immediately. They assert that studying psychiatric categories lacking biological validity blocks the discovery of brain bases for psychopathology and thus cannot lead to effective medical treatments for specific psychiatric symptoms (Cuthbert and Insel 2013;Insel et al. 2010;Lilienfeld and Treadway 2016;Yee et al. 2015). Against this RDoC imperative for biological validity, Weinberger et al. (2015) countered that current DSM-5 psychiatric behavioral diagnoses were valid when they yielded effective medical treatment, clear prognosis, and a life course specific to a diagnosis.Autism spectrum disorder (ASD) research has been productive (Dawson 2016;de la Torre-Ubieta et al. 2016;Szatmari et al. 2016), but no ASD research findings have met the validity criteria of Weinberger et al. (2015). DSM-5 ASD research has found no s...

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Section: Does Asd Have Neurobiological Validity?mentioning

confidence: 99%

Section: Genetic Syndromic Asd Has Been Found With Varied Brain Impaimentioning

confidence: 99%

Section: Genetic Syndromic Asd Has Been Found With Varied Brain Impaimentioning

confidence: 99%

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ASD Validity

Waterhouse

London

Gillberg

2016

Rev J Autism Dev Disord

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“…Of particular interest is the Shank family of postsynaptic scaffolding and anchoring proteins implicated in autism spectrum disorders (27). Shank1 and Shank3 each contain several RSK consensus phosphorylation sites (RXRXXS, where X is any amino acid) (28).…”

Section: Elevated Erk/rsk Signaling At Synapses Correlates With Incrementioning

confidence: 99%

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Sawicka

Pyronneau

Chao

et al. 2016

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

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Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.F ragile X syndrome (FXS) is the most common heritable form of intellectual disability and a leading genetic cause of autism. Individuals with FXS typically suffer from a range of cognitive and behavioral deficits that can include anxiety, stereotypic movements, hyperactivity, seizures, and aggression, as well as social deficits typical of autism (1). FXS is caused by transcriptional silencing or mutation of the FMR1 gene encoding the RNA-binding protein, FMRP (fragile X mental retardation protein). FMRP binds to >1,000 mRNAs, including transcripts encoding both preand postsynaptic proteins important for synaptic function, and represses their translation via ribosome stalling (2). Loss of FMRP expression in fragile X syndrome would be expected to cause translational derepression of these target mRNAs.FMRP is strategically localized to dendrites, dendritic spines, axons, and cell bodies to control protein synthesis. Loss of FMRP causes enhanced protein synthesis, which can lead to altered spine morphology, synaptic circuits, and synaptic function with robust effects on higher cognitive function. The excessive, unchecked protein synthesis and impaired stimulus-induced protein synthesis are considered to be major contributors to the pathophysiology of fragile X (3-5). Increased protein synthesis has been demonstrated in whole-animal st...

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“…Rare mutations-ASD include mutations in synaptic proteins such as ProSAPs/SHANKS proteins (with a crucial role in the assembly of the postsynaptic density during synaptogenesis, in synaptic plasticity and in the regulation of dendritic spine morphology) [72][73][74]; synaptic vesicle-associated proteins (SYN2 gene) [75]; and neuroligins/neurexins (synaptic cell adhesion molecules) for excitatory glutamatergic and inhibitory GABAergic synapses [neurexins (NRXN) (trigger postsynaptic differentiation), and neuroligins (NLGN) (trigger presynaptic differentiation)] [76] and play a pivotal role in synaptic function, especially at GABAergic synapses [77]. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, and NLGN4 on the X chromosome [50,78,79], NRXN1 on chromosome 2p16 [80], CNTNAP2 on chromosome 7q35 [81], and SHANK3 on chromosome 22q13 [51,82].…”

Section: Molecular Pathways Asd: "Developmental Synaptopathies"mentioning

confidence: 99%

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders

Cited by 150 publications

References 82 publications

ASD Validity

ASD Validity

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

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