Eugenio Medea Scientific Institute

Bosisio Parini, Italy

Eugenio Medea Scientific Institute

Bosisio Parini, Italy
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The research, which is featured in the April 1 issue of the Journal of Cell Science, is the first to show how the function of neurons is impaired by specific genetic defects that have been proven to cause HSP, a group of inherited neurological disorders that affect about 20,000 people in the United States. Those with HSP suffer from numbness and weakness in the legs and feet due to progressive deterioration of the neurons that carry signals from the brain to the spinal column, and Rice researchers hope that a better understanding of the root causes of HSP could lead to improved treatments. The new study is the latest to stem from a groundbreaking series of discoveries about HSP that have come from the laboratory of Rice biochemist James McNew since 2009. The new research was done in collaboration with the lab of fellow Rice biochemist Michael Stern and involved thousands of painstaking experiments by graduate students Jimmy Summerville, from Stern's group, and Joseph Faust, from McNew's. Summerville and Faust, co-lead authors of the new study, created dozens of mutant strains of the fruit fly Drosophila melanogaster, which has analogous genes to two human genes—atlastin and reticulon—that are known to cause HSP. By selectively mutating genes in the flies, Summerville and Faust manipulated the amount of the proteins atlastin and reticulon made in the flies' nerve cells. Both proteins are known to play roles in building and maintaining the structural framework of the endoplasmic reticulum (ER). The ER is an interconnected network of tubules and sheets that provide a cell with numerous critical functions. The research highlights the functional importance of the overall architecture and structure of the ER network. "This work is foundational in the sense that we now understand, at a mechanistic level, how ER structure influences the ability of a neuron to send a signal," McNew said. "That was unknown before. The ER is an essential organelle. Our cells need it to function correctly, and this study shows how a couple of specific changes to the ER can dramatically influence the ways that neurons 'talk' to muscles." HSP can be caused by defects in more than 70 genes, but defects to the atlastin gene have been linked to as many as 10 percent of HSP cases. Reticulon defects also can cause HSP, but the exact mechanisms by which these genes cause neurological problems are unclear. McNew began studying atlastin almost a decade ago, and in 2009 he and Italian scientist Andrea Daga of the Eugenio Medea Scientific Institute discovered that atlastin was a fusion protein that helped join together ER membranes. At the time, scientists knew that atlastin was associated with HSP, but its role as a membrane fusion protein was wholly unexpected because membrane fusion proteins were relatively rare and were all thought to operate in the same way. Scientists had never encountered a protein like atlastin, which is an enzyme that uses chemical energy to drive fusion. "Atlastin was completely different than any other membrane fusion protein, so we really had to start from scratch to determine how it worked," McNew said. Based on its role as a membrane fusion protein, McNew and colleagues hypothesized that atlastin was a key player in helping to form and maintain a healthy ER network in cells. Prior to the 2009 discovery, McNew's lab had used yeast as a model organism to study other fusion proteins. To study atlastin, he needed to adopt a new model organism, the fruit fly. As luck would have it, McNew's office in Rice's BioScience Research Collaborative was next door to Stern's, the leader of one of Rice's best-known groups for fruit fly research. The two researchers and their graduate students began collaborating, and McNew won a grant from the National Institutes of Health in 2011 to fund the experiments that Summerville and Faust carried out to study how atlastin influenced behavior at the cellular level. Stern said reticulon was thrown into the mix because it's also known to affect ER shape and structure, and because it sometimes counteracts atlastin. "One does one thing, and the other does another," he said. "They sort of work in opposition." Summerville and Faust first created three mutant strains of Drosophila: one that lacked the atlastin gene, another that lacked the reticulon gene and a third that lacked both genes. They then created dozens of subcategories of each type by adding back genes that would express one or more of the missing proteins in specific amounts and in specific tissues. They also created a new method for expressing a fluorescent tag in the ER so they could examine the resulting ER structure in Drosophila neuronal cells. In particular, they concentrated on the longest neurons in the flies' bodies, cells that stretched about 2 millimeters from end to end. These neurons are analogous to the human neurons that connect the spinal cord to the lower legs, which are immediately downstream of the corticospinal neurons that are known to misfunction in HSP patients. "These neurons are the longest cells in the human body," McNew said. "They can be up to a meter or more in length, and the hypothesis has long been that because these neurons are so long, they are somehow more susceptible to whatever ER defects result from the loss of atlastin or reticulon. "In fact, that is exactly what we found. Faust's imaging of the ER structure in the synapse found that the shape and look of the ER changed dramatically when atlastin was knocked out. Under normal conditions, the ER in the synapse forms a basket-like shape, and without atlastin, that structure is completely missing, and you just have diffuse ER material that is devoid of structure," McNew said. Stern said, "Even just seeing that there was a complex structure of ER within the nerve terminals was completely unknown before." Summerville's measurements of electrophysiological function also showed that neurons with these misshapen synapses released fewer neurotransmitters needed to activate attached muscles. The reticulon tests weren't as conclusive. While clear decreases in neuron function were observed when reticulon was absent, the team could not discern a visual difference in the ER structure when the protein was absent. Stern said the structural changes are so minute that they might only show up under a stronger microscope. Stern credited the success of the project to Summerville and Faust's determination and persistence. He said they had to improvise, in part because atlastin proved finicky to manipulate. "Normally, in a knockout study like this, you examine what happens in the negative case, where none of the protein is present, and then you make genetic manipulations to add back protein in specific tissues. This often leads to overexpression, where you have two or three or five times more protein than normal," Stern said. But this approach did not work for atlastin. Summerville found that even the slightest alterations in atlastin levels often caused the flies to die before they could be tested. "I think that's interesting scientifically," Stern said. "That says something about atlastin. But it also made Jimmy's life very difficult because it denied him the use of many of the tools that scientists take for granted when they do this type of study." While the new paper revealed some aspects of neuronal structure that had not yet been seen, Stern and McNew said they expect their follow-up study, which is already under way, to provide even more compelling results in terms of the mechanism by which HSP operates. "I view this paper as an introductory paper," Stern said. "We did the characterization that you need to do to get the foundation of what's going on. That turns this into science, and it sets the stage for the experiments that we're doing now, which are aimed at answering the question of what this protein is doing, not only in nervous system function, but also in terms of how it might be affecting the patients with this disease." Explore further: Little-known protein found to be key player More information: J. Summerville et al. The effects of ER morphology on synaptic structure and function in Drosophila melanogaster, Journal of Cell Science (2016). DOI: 10.1242/jcs.184929

Battaglia M.,Vita-Salute San Raffaele University | Battaglia M.,San Raffaele Hospital | Zanoni A.,Vita-Salute San Raffaele University | Taddei M.,Vita-Salute San Raffaele University | And 8 more authors.
Depression and Anxiety | Year: 2012

Background Cross-sectional studies report biased reactivity to facial expressions among shy children, anxious adolescents, and adults with social anxiety disorder (SAD). It remains unknown whether cerebral reactivity to facial expressions can predict longitudinally the development of SAD in adolescence and characterize the degree of social anxiety among the general population of adolescents. Methods In a longitudinal study of 21 general population volunteers characterized for behavioral and genetic variables, N400 event-related potentials, and 3-Tesla fMRI activations in response to happy/neutral/angry expressions were acquired at age 8-9 and 14-15, respectively. Results By stepwise regression, N400 amplitudes acquired at age 8-9 predicted the number of DSM-IV SAD symptoms at age 14-15, with the sole, significant (P =.018) contribution of the "anger" condition. Factorial ANOVA revealed increased (Voxel-Level P (FWE) range:.02-.0001) bilateral fMRI activations of several brain areas, including the amygdala, in response to facial expressions compared to a fixation cross. The number of symptoms of DSM-IV SAD was positively correlated with left amygdala response to angry (P (FWE) =.036) and neutral (P (FWE) =.025) facial expressions. Factorial ANOVA revealed that the 5-HTTLPR -S allele was associated with heightened left amygdala response to anger (P (FWE) =.05). Conclusion Cerebral reactivity to facial expressions, anger especially, measured at different developmental stages by different techniques is associated with adolescence SAD. The 5-HTTLPR genotype affects the neural processing of interpersonal affective stimuli during development. © 2011 Wiley-Liss, Inc.

Debattisti V.,Venetian Institute of Molecular Medicine | Pendin D.,Eugenio Medea Scientific Institute | Ziviani E.,University of Geneva | Daga A.,Eugenio Medea Scientific Institute | And 2 more authors.
Journal of Cell Biology | Year: 2014

Ablation of the mitochondrial fusion and endoplasmic reticulum (ER)-tethering protein Mfn2 causes ER stress, but whether this is just an epiphenomenon of mitochondrial dysfunction or a contributor to the phenotypes in mitofusin (Mfn)-depleted Drosophila melanogaster is unclear. In this paper, we show that reduction of ER dysfunction ameliorates the functional and developmental defects of flies lacking the single Mfn mitochondrial assembly regulatory factor (Marf). Ubiquitous or neuron- and muscle-specific Marf ablation was lethal, altering mitochondrial and ER morphology and triggering ER stress that was conversely absent in flies lacking the fusion protein optic atrophy 1. Expression of Mfn2 and ER stress reduction in flies lacking Marf corrected ER shape, attenuating the developmental and motor defects. Thus, ER stress is a targetable pathogenetic component of the phenotypes caused by Drosophila Mfn ablation. © 2014 Debattisti et al.

Bellani M.,University of Verona | Nobile M.,Eugenio Medea Scientific Institute | Bianchi V.,Eugenio Medea Scientific Institute | Van Os J.,Maastricht University | And 2 more authors.
Epidemiology and Psychiatric Sciences | Year: 2013

In a short series of articles, we will review the evidence for genotype by environment interaction (G × E) in developmental psychopathology. We will focus specifically on the characteristics of types of exposure assessed with respect to both their methods and findings. This article aims to review the studies exploring the moderating role of serotonin transporter on the effect of environmental adversities over time, particularly during childhood and adolescence, which is when level of internalizing symptoms and prevalence of mood disorders change substantially. Environmental adversities will not include abuse and maltreatment that have been reviewed before (see Bellani et al. 2012) and child's broader social ecology that will be reviewed in the next section. Copyright © Cambridge University Press 2012.

PubMed | Eugenio Medea Scientific Institute, University of L'Aquila, University of Pisa, University of Naples and University of Brescia
Type: Journal Article | Journal: Schizophrenia research | Year: 2016

Impaired premorbid adjustment has been reported in patients with schizophrenia, generally in association with unfavorable aspects of the illness (e.g., poor outcome and severe negative symptoms). Several studies attempted to define the domains of premorbid dysfunction associated with negative symptoms and poor outcome; however, most of them assessed broadly defined negative symptoms. The present study was aimed to characterize premorbid functioning in a group of patients with deficit schizophrenia (DS), characterized by the presence of at least two primary and persistent negative symptoms (PPNS), and one of patients with a diagnosis of schizophrenia who did not meet criteria for DS (NDS). The presence of emotional/behavioral problems during childhood was investigated using the Childhood Behavior Checklist (CBCL) in both patient groups and in their respective healthy siblings. The Premorbid Adjustment Scale (PAS) was also used to assess premorbid functioning during childhood in the two patient groups. PPNS were also treated as a continuous variable and correlated with the indices of premorbid functioning regardless the DS/NDS categorization. DS patients, as compared to NDS, showed higher scores on the CBCL subscale Withdrawn. Both DS and NDS patients showed, as compared to their healthy siblings, a greater impairment on almost all CBCL subscales. PAS findings revealed that DS patients had poorer premorbid adjustment than NDS. No significant correlation between premorbid functioning and PPNS was observed. These findings support the hypothesis that DS has a different developmental trajectory with respect to NDS, and that premorbid adjustment is one of the essential aspects of its characterization.

Spatola C.A.M.,Vita-Salute San Raffaele University | Rende R.,Brown University | Battaglia M.,Vita-Salute San Raffaele University | Battaglia M.,San Raffaele Institute | Battaglia M.,Eugenio Medea Scientific Institute
European Child and Adolescent Psychiatry | Year: 2010

Inasmuch as the newly established DSM-oriented CBCL/6-18 scales are to be increasingly employed o assess clinical/high-risk populations, it becomes important to explore their aetiology both within the normal- and the extreme range of variation in general population samples and to compare the results obtained in different age groups. We investigated by the Quantitative Maximum Likelihood, the De Fries-Fulker, and the Ordinal Maximum Likelihood methods the genetic and environmental influences upon the five DSM-oriented CBCL/6-18 scales in 796 twins aged 8-17 years belonging to the general population-based Italian Twin Registry. When children were analysed together regardless of age, most best-fitting solutions yielded genetic and non-shared environmental factors as the sole influences for DSMoriented CBCL/6-18 behaviours, both for the normal and the extreme variations. When analyses were conducted separately for two age groups, shared environmental influences emerged consistently for Affective and Anxiety Problems in children aged 8-11. Oppositional-Defiant, Attention Deficit/Hyperactivity, and Conduct Problems appeared-with few exceptions-influenced only by genetic and non-shared environmental factors in both age groups, according to all three computational approaches. The De Fries-Fulker method appeared to be more sensitive in detecting shared environmental effects. Analysing the same set of data with different analytic approaches leads to better-balanced views on the aetiology of psychopathological behaviours in the developmental years. © Springer-Verlag 2010.

Romaniello R.,Eugenio Medea Scientific Institute | Tonelli A.,Eugenio Medea Scientific Institute | Arrigoni F.,Eugenio Medea Scientific Institute | Baschirotto C.,Eugenio Medea Scientific Institute | And 4 more authors.
Developmental Medicine and Child Neurology | Year: 2012

Neurological disorders characterized by abnormal neuronal migration, organization, axon guidance, and maintenance have recently been associated with missense and splice-site mutations in the genes encoding α- and β-tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. We found a novel heterozygous mutation c.419G>C in exon 4 of the gene encoding TUBB2B in a female with microcephaly, agenesis of the corpus callosum, open-lip schizencephaly of the left parietal lobe, extensive polymicrogyria, basal ganglia and thalami dysmorphisms, and vermis and right third nerve hypoplasia. The missense change results in a glycine to alanine substitution; the mutated residue falls within an invariant glycine-rich region and therefore is likely to result in impaired protein function and possibly microtubule formation. This study expands the spectrum of brain malformations associated with mutations in the β-tubulin gene TUBB2B, supporting its critical role in migration/organization and axon guidance processes. In addition, it suggests a possible genetic aetiology of schizencephaly, thus strengthening the hypothesis that there is a common pathophysiological base in polymicrogyria and schizencephaly. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Tavano A.,Eugenio Medea Scientific Institute | Borgatti R.,Eugenio Medea Scientific Institute
Cortex | Year: 2010

We compared the neurobehavioral profiles of children with Joubert syndrome (JS participants), a rare autosomal recessive condition characterized on magnetic resonance imaging (MRI) by hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations, and children with malformations confined to the cerebellar vermis and one or both hemispheres (Cerebellar malformations - CM participants). We aimed at investigating the influence of anatomo-clinical similarities (vermian malformation) and differences (intact cerebellar hemispheres vs sparing of the pons, respectively) with respect to cognitive, linguistic and emotional development, assuming as a reference framework the Cerebellar Cognitive Affective Syndrome (CCAS). Results show that severe to moderate mental retardation is infrequent in JS children, while it is present in more than half the sample of CM children. Affect development was generally preserved in JS, in high-functioning CM individuals and also in some of the CM children with moderate mental retardation, which raised questions as to the role of a cerebellar vermis lesion in determining affect disorders. Further, cognitive and linguistic profiles on both intellectual and neuropsychological evaluations provided evidence for distinct patterns of peaks and valleys in the two groups, with JS children being significantly more impaired in language and verbal working memory and CM individuals showing a significant impairment of executive functions and emotional development. The overall evidence provides support for an important role of cerebellar structures per se in shaping emotional, cognitive and linguistic development, when vermian lesions are associated to cerebellar hemispheric lesions. Cerebellar vermis and brainstem lesions instead appear to have a major impact on motor-related skills, including oro-motor abilities and verbal working memory. © 2009 Elsevier Srl.

Tremolizzo L.,University of Milan Bicocca | Conti E.,University of Milan Bicocca | Bomba M.,University of Milan Bicocca | Uccellini O.,University of Milan Bicocca | And 8 more authors.
World Journal of Biological Psychiatry | Year: 2014

Objectives. The one-carbon metabolism, also known as methionine- homocysteine cycle, governs the dynamics of DNA methylation, epigenetically regulating gene expression, and has been reported altered in anorexia nervosa (AN) adult patients. The aim of this study consisted in assessing whole-blood DNA methylation in adolescent AN patients, assessing its significance in relationship to clinical and hormonal variables. Methods. Whole-blood global DNA methylation was measured as incorporation of [3H]dCTP following HpaII cut in 32 adolescent females affected by restrictive type AN and compared to 13 healthy controls. Homocysteine, vitamin B12 and folate plasma levels were assessed as well as fasting plasma levels of leptin and steroid hormones. Clinical variables, including severity and associate states and traits, were assessed by means of the EDI-3, CDI and STAI-Y scales. Results. We confirm that whole-blood global DNA methylation is modestly albeit significantly reduced in AN adolescents with respect to controls, correlating with plasma leptin and steroid hormone levels. Conversely, clinical traits did not correlate with the outcome variable. Conclusions. A better definition of the epigenetic dysregulation underlying AN pathology or vulnerability might lead to develop useful markers for diagnosis, prognostic classification and tailored therapeutic interventions in these vulnerable patients since the earliest phases of their disease. © 2014 Informa Healthcare.

Bellina M.,Eugenio Medea Scientific Institute | Brambilla P.,University of Udine | Brambilla P.,Eugenio Medea Scientific Institute | Garzitto M.,Eugenio Medea Scientific Institute | And 5 more authors.
European Child and Adolescent Psychiatry | Year: 2013

The majority of studies examining associations between clinical-diagnostic and empirical-quantitative approaches have concentrated only on the target diagnosis without taking into account any possible co-variation of psychopathological traits, which is intrinsic to child psychopathology. The ability of child behaviour checklist (CBCL) DSM-oriented scales (DOSs) to predict target and other DSM diagnoses, taking into consideration the covariation of psychopathological traits, was analysed by logistic regression analysis. Corresponding odds ratio (OR) was used as indicator of the strength of the relationship between the clinical score in DOSs and the presence of DSM-IV diagnoses. Logistic regression allowed us to consider multiple scales simultaneously, thus addressing the problem of co-occurrence of psychopathological traits, and to include gender and age as covariates. The sample consisted of 360 children and adolescents aged 6-16 years, consecutively referred for behavioural and emotional problems. As a whole, the CBCL DOSs seem to be more specific but with a weaker association with DSM-IV diagnoses than syndrome scales, and with some distinctive features: clinical scores in the anxiety DOS suggest a diagnosis of both anxiety and mood disorder; clinical scores in the somatic problems DOS are very strong and specific predictors for diagnosis of separation anxiety disorder; clinical scores in the oppositional defiant problems DOS are not only predictors of the oppositional defiant disorder but are also strong predictors of generalized anxiety disorder; clinical scores in the conduct problems DOS are a specific and strong predictor for oppositional defiant disorder. Results confirm the clinical usefulness of CBCL and suggest using both syndrome and DOS scales for a complete and accurate assessment of children and adolescents. © 2012 Springer-Verlag Berlin Heidelberg.

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