Carlo Sala

Carlo Sala
Italian National Research Council | CNR · Institute of Neuroscience IN

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196
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Publications

Publications (196)
Article
Full-text available
Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype...
Article
The development of new therapeutic avenues that target the early stages of Alzheimer's disease (AD) is urgently necessary. ADAM10 is a sheddase that is involved in dendritic spine shaping and limits the generation of amyloid-β. ADAM10 endocytosis increases in the hippocampus of AD patients, resulting in the decreased postsynaptic localization of th...
Article
Full-text available
Background Dravet Syndrome is a severe childhood pharmaco-resistant epileptic disorder mainly caused by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that causes imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhance...
Article
Full-text available
Shank3 monogenic mutations lead to autism spectrum disorders (ASD). Shank3 is part of the glutamate receptosome that physically links ionotropic NMDA receptors to metabotropic mGlu5 receptors through interactions with scaffolding proteins PSD95–GKAP–Shank3–Homer. A main physiological function of the glutamate receptosome is to control NMDA synaptic...
Article
Calcineurin (CaN), acting downstream of intracellular calcium signals, orchestrates cellular remodeling in many cellular types. In astrocytes, major homeostatic players in the central nervous system (CNS), CaN is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we rep...
Preprint
Full-text available
Background: Dravet Syndrome is a severe childhood pharmaco-resistant epileptic disorder mainly caused by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhance...
Article
Various neuroimaging approaches have reported alterations in brain connectivity in patients with autism spectrum disorder (ASD). Nevertheless, specific cellular and molecular mechanisms underlying these alterations remain to be elucidated. In the present Editorial, we highlight an article in the current issue of the Journal of Neurochemistry that p...
Preprint
Dravet Syndrome is a severe childhood pharmacoresistant epileptic disorder caused mainly by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic t...
Article
Full-text available
Human mutations and haploinsufficiency of the SHANK family genes are associated with autism spectrum disorders (ASD) and intellectual disability (ID). Complex phenotypes have been also described in all mouse models of Shank mutations and deletions, consistent with the heterogeneity of the human phenotypes. However, the specific role of Shank protei...
Article
The N-methyl-d-aspartate (NMDA) receptor, among the ionotropic glutamate receptors, are fundamental to integrating and transducing complex signaling in neurons. Glutamate activation of these receptors mediates intracellular signals essential to neuronal and synaptic formation and synaptic plasticity and also contribute to excitotoxic processes in s...
Article
Full-text available
Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high-confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here tha...
Preprint
Full-text available
Shank3 monogenic mutations lead to Autism Spectrum Disorders (ASD). Shank3 is part of the glutamate receptosome that physically links ionotropic NMDA receptors to metabotropic mGlu5 receptors through interactions with scaffolding proteins PSD95-GKAP-Shank3-Homer. A main physiological function of the glutamate receptosome is to control NMDA synaptic...
Article
Full-text available
Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. The comprehension of the mechanisms of...
Article
Full-text available
Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. The comprehension of the mechanisms of...
Preprint
Full-text available
Calcineurin (CaN), acting downstream of intracellular calcium signals, orchestrates cellular remodelling in many cellular types. In astrocytes, principal homeostatic cells in the central nervous system (CNS), CaN is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we...
Article
Two major processes tightly regulate protein synthesis, the initiation of mRNA translation and elongation phase that mediates the movement of ribosomes along the mRNA. The elongation phase is a high energy-consuming process, and it is mainly regulated by the eukaryotic elongation factor 2 kinase (eEF2K) activity that phosphorylates and inhibits eEF...
Article
Hybrid interfaces between living cells and nano/microstructured scaffolds have huge application potential in biotechnology, spanning from regenerative medicine and stem cell therapies to localized drug delivery and from biosensing and tissue engineering to neural computing. However, 3D architectures based on semiconducting polymers, endowed with re...
Preprint
Full-text available
Cre-Lox manipulation is the gold standard for cell-specific expression or knockout of selected genes. However, it is not unusual to deal with conditions of low Cre expression or transient activation, which can often go undetected by conventional Cre- reporters. We designed Beatrix, a general-purpose tool specifically devised to amplify weak Cre rec...
Article
A common feature of several psychiatric disorders is the attentional impairment. eEF2K‐/‐, IL1RAPL1‐/‐ and SHANK3Δ11‐/‐ mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual...
Article
Since the first observation that described a patient with a mutation in IL1RAPL1 gene associated with intellectual disability in 1999, the function of IL1RAPL1 have been extensively studied by a number of laboratories. In this review, we summarize all the major data describing the synaptic and neuronal functions of IL1RAPL1 and recapitulate most of...
Article
Full-text available
We here investigated the effects of overexpressed superoxide dismutase (SOD)1 and amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants G93A and G147S in Neuro 2A (N2A) cell lines, and found a three-fold increase in lamellipodia either in cells cultured under differentiated or undifferentiated growth conditions. In undifferentiated N2A cells, SOD...
Article
The term “Shankopathies” identifies neurodevelopmental diseases, such as autism Spectrum Disorders (ASD), Intellectual Disability (ID), and schizophrenia (SCZ) caused by deletion or mutations of SHANK/ProSAP genes. The three SHANK genes code for a postsynaptic scaffold protein which has a main function of regulating synaptic formation, development...
Article
Mutations and deletions of the interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene, located on the X chromosome, are associated with intellectual disability (ID) and autism spectrum disorder (ASD). IL1RAPL1 protein is located at the postsynaptic compartment of excitatory synapses and plays a role in synapse formation and stabilization....
Chapter
Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects more than 1% of children per current estimates. It has been characterised by the following two core behavioural phenotypes: (1) deficits in social interaction and communication and (2) repetitive behaviours, restricted interests and activities. Due to the complex nature o...
Article
Full-text available
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Article
Full-text available
Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interact...
Data
Supplementary Figures and Supplementary Tables
Article
Full-text available
Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome, autism spectrum disorder (ASD), and intellectual disability. Although, a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the post-synaptic protein scaffold, the molecular processes...
Data
Complete Western blot membranes. Complete membranes of the Western blots presented in Figure 1: (A,B) Subcellular fractions derived from striatal (A) or hippocampal (B) PSD isolation as indicated: Homogenate (Ho), Purified homogenate (S1), Crude membrane fraction (P2), Cytosol (S2), Synaptosomes (Syn), PSD and Synaptic cytosol (S3) from WT and Shan...
Data
Further characterization of the proteomic dataset. (A) Dynamic range of detected PSD proteins in the striatum (STR) and hippocampus (HIP) of WT and Shank3Δ11-/- mutant (KO) mice. (B) Overlap of proteins identified in the PSDs derived from the striatum (STR) and hippocampus (HIP) of WT and Shank3Δ11-/- mutant (KO) mice. Only proteins that have been...
Data
Shank3 genetic targeting strategy and resulting pattern of Shank3 isoforms still present in Shank3Δ11-/- mutant mice. (A) Schematic illustration of the murine Shank3 gene (boxes represent respective exons) showing the deletion of exon 11 (indicated in red) and the remaining Shank3 isoforms based on the review by Jiang and Ehlers (2013) excluding al...
Data
Analysis of Shank3 isoforms still present in Shank3Δ11-/- mutant mice. (A) Schematic illustration of the murine Shank3 gene (boxes represent respective exons) showing the deletion of exon 11 (indicated in red) and the remaining Shank3 isoforms based on the review by Jiang and Ehlers (2013) excluding alternative splice variants (ANK: N-terminal anky...
Chapter
Synaptic connections are established between neurons during development of the nervous system after axon path finding and dendrite development. Synapse development is mediated by specific synaptic cell adhesion molecules (SCAMs) that accumulate at pre- and postsynaptic sites and trigger synaptic differentiation through interactions with intra- and...
Article
Full-text available
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain...
Book
Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability provides the latest information on Autism spectrum disorders (ASDs), the lifelong neurodevelopmental disorders that present in early childhood and affect how individuals communicate and relate to others and their surroundings. In addition, three quarters of AS...
Article
Full-text available
The current dogma suggests that the formation of long-term memory (LTM) is dependent on protein synthesis but persistence of the memory trace is not. However, many of the studies examining the effect of protein synthesis inhibitors (PSIs) on LTM persistence were performed in the hippocampus, which is known to have a time-dependent role in memory st...
Article
SHANK3 (also called PROSAP2) genetic haploinsufficiency is thought to be the major cause of neuropsychiatric symptoms in Phelan-McDermid syndrome (PMS). PMS is a rare genetic disorder that causes a severe form of intellectual disability (ID), expressive language delays and other autistic features. Furthermore, a significant number of SHANK3 mutatio...
Article
In astrocytes, the intracellular calcium (Ca(2+)) signaling mediated by activation of metabotropic glutamate receptor 5 (mGlu5) is crucially involved in the modulation of many aspects of brain physiology, including gliotransmission. Here, we find that the mGlu5-mediated Ca(2+)signaling leading to release of glutamate is governed by mGlu5 interactio...
Article
Full-text available
SHANK3 (also called PROSAP2) genetic haploinsufficiency is thought to be the major cause of neuropsychiatric symptoms in Phelan-McDermid syndrome (PMS). PMS is a rare genetic disorder that causes a severe form of intellectual disability (ID), expressive language delays and other autistic features. Furthermore, a significant number of SHANK3 mutatio...
Article
Full-text available
Alterations in the balance of inhibitory and excitatory synaptic transmission have been implicated in the pathogenesis of neurological disorders such as epilepsy. Eukaryotic elongation factor 2 kinase (eEF2K) is a highly regulated, ubiquitous kinase involved in the control of protein translation. Here, we show that eEF2K activity negatively regulat...
Article
Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a nu...
Article
Full-text available
Synapse and dendrite deficits induced by mutations in the X-linked intellectual disability gene Il1rapl1 Caterina Montani, Mariana Ramos-Brossier, Pierre Billuart, Carlo Sala Mutations and deletions of Interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene, localized on X chromosome, are associated to intellectual disability (ID) and autis...
Article
Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work is to characterize the synap...
Article
Full-text available
Loss of ataxia telangiectasia mutated (ATM) kinase, a key factor of the DNA damage response (DDR) pathway, causes the cancer predisposing and neurodegenerative syndrome ataxia-telangiectasia (A-T). To investigate the mechanisms of neurodegeneration, we have reprogrammed fibroblasts from ATM-null A-T patients and normal controls to pluripotency (hum...
Article
Full-text available
Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecu...
Article
Full-text available
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study, we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic anal...
Article
Full-text available
Local protein synthesis in dendrites enables neurons to selectively change the protein complement of individual postsynaptic sites. Though it is generally assumed that this mechanism requires tight translational control of dendritically transported mRNAs, it is unclear how translation of dendritic mRNAs is regulated. We have analyzed here translati...
Article
Full-text available
Neuronal activity results in long lasting changes in synaptic structure and function by regulating mRNA translation in dendrites. These activity dependent events yield the synthesis of proteins known to be important for synaptic modifications and diverse forms of synaptic plasticity. Worthy of note, there is accumulating evidence that the eukaryoti...
Article
A number of mutated genes that code for proteins concerned with brain synapse function and circuit formation have been identified in patients affected by intellectual disability syndromes over the last fifteen years. These genes are involved in synapse formation and plasticity, the regulation of dendritic spine morphology, the regulation of the syn...
Article
Full-text available
The introduction of high-resolution time lapse imaging and molecular biological tools has changed dramatically the rate of progress towards the understanding of the complex structure-function relations in synapses of central spiny neurons. Standing issues, including the sequence of molecular and structural processes leading to formation, morphologi...
Article
Full-text available
A complex and still not comprehensively resolved panel of transmembrane proteins regulates the outgrowth and the subsequent morphological and functional development of neuronal processes. In order to gain a more detailed description of these events at the molecular level, we have developed a cell surface biotinylation assay to isolate, detect and q...
Article
The molecular mechanisms underlying neuronal synapses formation, growth, and maturation have been extensively analyzed by biochemical, genetic, and imaging studies. The postsynaptic density (PSD), localized at the excitatory synapses, is a specialized protein complex whose functions include the regulation of synapse formation and function, the cont...
Article
Read the full article Spikar, a novel drebrin-binding protein, regulates the formation and stabilization of dendritic spines' on doi:
Conference Paper
Lara Buscemi1,5, Vanessa Ginet1, Francesco Petrelli1, Corrado Calì1,2, Paola Spagnuolo1, Carlo Sala3, Anita Truttmann4, Graham Knott2, Lorenz Hirt5, Julien Puyal1 and Paola Bezzi1 1. Dept of Fundamental Neurosciences, UNIL, 1005 Lausanne, Switzerland; 2. Interdisciplinary Electron Microscopy Center, EPFL, 1015 Lausanne, Switzerland;3. Institute of...
Article
Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by inse...
Article
Full-text available
Most human neuronal disorders are associated with genetic alterations that cause defects in neuronal development and induce precocious neurodegeneration. In order to fully characterize the molecular mechanisms underlying the onset of these devastating diseases, it is important to establish in vitro models able to recapitulate the human pathology as...
Article
Full-text available
Epigenetic mechanisms play important roles in brain development, orchestrating proliferation, differentiation and morphogenesis. Lysine-Specific Demethylase 1 (LSD1 also known as KDM1A and AOF2) is a histone modifier involved in transcriptional repression, forming a stable core complex with the corepressors CoREST, HDAC1/2. Importantly, in the mamm...