A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model / Hendrik WESSELING in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 41p. Titre : A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model Type de document : texte imprimé Auteurs : Hendrik WESSELING, Auteur ; Ype ELGERSMA, Auteur ; Sabine BAHN, Auteur Article en page(s) : 41p. Langues : Anglais (eng) Mots-clés : Animal model  Proteomics  Rapamycin  Srm  Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model [texte imprimé] / Hendrik WESSELING, Auteur ; Ype ELGERSMA, Auteur ; Sabine BAHN, Auteur . - 41p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 41p. Mots-clés : Animal model  Proteomics  Rapamycin  Srm  Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Identification of an age-dependent biomarker signature in children and adolescents with autism spectrum disorders / Jordan RAMSEY in Molecular Autism, (August 2013)  

Public ISBD [article]  inMolecular Autism > (August 2013) . - 18 p. Titre : Identification of an age-dependent biomarker signature in children and adolescents with autism spectrum disorders Type de document : texte imprimé Auteurs : Jordan RAMSEY, Auteur ; Paul C. GUEST, Auteur ; Jantine A.C. BROEK, Auteur ; Jeffrey C. GLENNON, Auteur ; Nanda N. ROMMELSE, Auteur ; Barbara FRANKE, Auteur ; Hassan RAHMOUNE, Auteur ; Jan K. BUITELAAR, Auteur ; Sabine BAHN, Auteur Année de publication : 2013 Article en page(s) : 18 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASDs) are neurodevelopmental conditions with symptoms manifesting before the age of 3, generally persisting throughout life and affecting social development and communication. Here, we have investigated changes in protein biomarkers in blood during childhood and adolescent development. Methods We carried out a multiplex immunoassay profiling analysis of serum samples from 37 individuals with a diagnosis of ASD and their matched, non-affected siblings, aged between 4 and 18 years, to identify molecular pathways affected over the course of ASDs. Results This analysis revealed age-dependent differences in the levels of 12 proteins involved in inflammation, growth and hormonal signaling. Conclusions These deviations in age-related molecular trajectories provide further insight into the progression and pathophysiology of the disorder and, if replicated, may contribute to better classification of ASD individuals, as well as to improved treatment and prognosis. The results also underline the importance of stratifying and analyzing samples by age, especially in ASD and potentially other developmental disorders. En ligne : http://dx.doi.org/10.1186/2040-2392-4-27 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=211 [article] Identification of an age-dependent biomarker signature in children and adolescents with autism spectrum disorders [texte imprimé] / Jordan RAMSEY, Auteur ; Paul C. GUEST, Auteur ; Jantine A.C. BROEK, Auteur ; Jeffrey C. GLENNON, Auteur ; Nanda N. ROMMELSE, Auteur ; Barbara FRANKE, Auteur ; Hassan RAHMOUNE, Auteur ; Jan K. BUITELAAR, Auteur ; Sabine BAHN, Auteur . - 2013 . - 18 p. Langues : Anglais (eng) in Molecular Autism > (August 2013) . - 18 p. Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASDs) are neurodevelopmental conditions with symptoms manifesting before the age of 3, generally persisting throughout life and affecting social development and communication. Here, we have investigated changes in protein biomarkers in blood during childhood and adolescent development. Methods We carried out a multiplex immunoassay profiling analysis of serum samples from 37 individuals with a diagnosis of ASD and their matched, non-affected siblings, aged between 4 and 18 years, to identify molecular pathways affected over the course of ASDs. Results This analysis revealed age-dependent differences in the levels of 12 proteins involved in inflammation, growth and hormonal signaling. Conclusions These deviations in age-related molecular trajectories provide further insight into the progression and pathophysiology of the disorder and, if replicated, may contribute to better classification of ASD individuals, as well as to improved treatment and prognosis. The results also underline the importance of stratifying and analyzing samples by age, especially in ASD and potentially other developmental disorders. En ligne : http://dx.doi.org/10.1186/2040-2392-4-27 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=211

Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders / Hendrik WESSELING in Molecular Autism, (July 2014)  

Public ISBD [article]  inMolecular Autism > (July 2014) . - p.1-17 Titre : Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders Type de document : texte imprimé Auteurs : Hendrik WESSELING, Auteur ; Paul C. GUEST, Auteur ; Chi-Ming LEE, Auteur ; Erik H.F. WONG, Auteur ; Hassan RAHMOUNE, Auteur ; Sabine BAHN, Auteur Article en page(s) : p.1-17 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo−/−) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. En ligne : http://dx.doi.org/10.1186/2040-2392-5-38 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276 [article] Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders [texte imprimé] / Hendrik WESSELING, Auteur ; Paul C. GUEST, Auteur ; Chi-Ming LEE, Auteur ; Erik H.F. WONG, Auteur ; Hassan RAHMOUNE, Auteur ; Sabine BAHN, Auteur . - p.1-17. Langues : Anglais (eng) in Molecular Autism > (July 2014) . - p.1-17 Index. décimale : PER Périodiques Résumé : Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo−/−) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. En ligne : http://dx.doi.org/10.1186/2040-2392-5-38 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276

Proteomic analysis of post mortem brain tissue from autism patients: evidence for opposite changes in prefrontal cortex and cerebellum in synaptic connectivity-related proteins / Jantine A.C. BROEK in Molecular Autism, (July 2014)  

Public ISBD [article]  inMolecular Autism > (July 2014) . - p.1-8 Titre : Proteomic analysis of post mortem brain tissue from autism patients: evidence for opposite changes in prefrontal cortex and cerebellum in synaptic connectivity-related proteins Type de document : texte imprimé Auteurs : Jantine A.C. BROEK, Auteur ; Paul C. GUEST, Auteur ; Hassan RAHMOUNE, Auteur ; Sabine BAHN, Auteur Article en page(s) : p.1-8 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism is a neurodevelopmental disorder characterized by impaired language, communication and social skills. Although genetic studies have been carried out in this field, none of the genes identified have led to an explanation of the underlying causes. Here, we have investigated molecular alterations by proteomic profiling of post mortem brain samples from autism patients and controls. The analysis focussed on prefrontal cortex and cerebellum as previous studies have found that these two brain regions are structurally and functionally connected, and they have been implicated in autism. En ligne : http://dx.doi.org/10.1186/2040-2392-5-41 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276 [article] Proteomic analysis of post mortem brain tissue from autism patients: evidence for opposite changes in prefrontal cortex and cerebellum in synaptic connectivity-related proteins [texte imprimé] / Jantine A.C. BROEK, Auteur ; Paul C. GUEST, Auteur ; Hassan RAHMOUNE, Auteur ; Sabine BAHN, Auteur . - p.1-8. Langues : Anglais (eng) in Molecular Autism > (July 2014) . - p.1-8 Index. décimale : PER Périodiques Résumé : Autism is a neurodevelopmental disorder characterized by impaired language, communication and social skills. Although genetic studies have been carried out in this field, none of the genes identified have led to an explanation of the underlying causes. Here, we have investigated molecular alterations by proteomic profiling of post mortem brain samples from autism patients and controls. The analysis focussed on prefrontal cortex and cerebellum as previous studies have found that these two brain regions are structurally and functionally connected, and they have been implicated in autism. En ligne : http://dx.doi.org/10.1186/2040-2392-5-41 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276

Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome / Hannah STEEB in Molecular Autism, (January 2014)  

Public ISBD [article]  inMolecular Autism > (January 2014) Titre : Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome Type de document : texte imprimé Auteurs : Hannah STEEB, Auteur ; Jordan RAMSEY, Auteur ; Paul C. GUEST, Auteur ; Pawel STOCKI, Auteur ; Jason COOPER, Auteur ; Hassan RAHMOUNE, Auteur ; Erin INGUDOMNUKUL, Auteur ; Bonnie AUYEUNG, Auteur ; Liliana RUTA, Auteur ; Simon BARON-COHEN, Auteur ; Sabine BAHN, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The higher prevalence of Asperger Syndrome (AS) and other autism spectrum conditions in males has been known for many years. However, recent multiplex immunoassay profiling studies have shown that males and females with AS have distinct proteomic changes in serum. Here, we analysed sera from adults diagnosed with AS (males=14, females=16) and controls (males=13, females=16) not on medication at the time of sample collection, using a combination of multiplex immunoassay and shotgun label-free liquid chromatography mass spectrometry (LC-MSE). The main objective was to identify sex-specific serum protein changes associated with AS. Multiplex immunoassay profiling led to identification of 16 proteins that were significantly altered in AS individuals in a sex-specific manner. Three of these proteins were altered in females (ADIPO, IgA, APOA1), seven were changed in males (BMP6, CTGF, ICAM1, IL-12p70, IL-16, TF, TNF-alpha) and six were changed in both sexes but in opposite directions (CHGA, EPO, IL-3, TENA, PAP, SHBG). Shotgun LC-MSE profiling led to identification of 13 serum proteins which had significant sex-specific changes in the AS group and, of these, 12 were altered in females (APOC2, APOE, ARMC3, CLC4K, FETUB, GLCE, MRRP1, PTPA, RN149, TLE1, TRIPB, ZC3HE) and one protein was altered in males (RGPD4). The free androgen index in females with AS showed an increased ratio of 1.63 compared to controls.CONCLUSION:Taken together, the serum multiplex immunoassay and shotgun LC-MSE profiling results indicate that adult females with AS had alterations in proteins involved mostly in lipid transport and metabolism pathways, while adult males with AS showed changes predominantly in inflammation signalling. These results provide further evidence that the search for biomarkers or novel drug targets in AS may require stratification into male and female subgroups, and could lead to the development of novel targeted treatment approaches. En ligne : http://dx.doi.org/10.1186/2040-2392-5-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome [texte imprimé] / Hannah STEEB, Auteur ; Jordan RAMSEY, Auteur ; Paul C. GUEST, Auteur ; Pawel STOCKI, Auteur ; Jason COOPER, Auteur ; Hassan RAHMOUNE, Auteur ; Erin INGUDOMNUKUL, Auteur ; Bonnie AUYEUNG, Auteur ; Liliana RUTA, Auteur ; Simon BARON-COHEN, Auteur ; Sabine BAHN, Auteur. Langues : Anglais (eng) in Molecular Autism > (January 2014) Index. décimale : PER Périodiques Résumé : The higher prevalence of Asperger Syndrome (AS) and other autism spectrum conditions in males has been known for many years. However, recent multiplex immunoassay profiling studies have shown that males and females with AS have distinct proteomic changes in serum. Here, we analysed sera from adults diagnosed with AS (males=14, females=16) and controls (males=13, females=16) not on medication at the time of sample collection, using a combination of multiplex immunoassay and shotgun label-free liquid chromatography mass spectrometry (LC-MSE). The main objective was to identify sex-specific serum protein changes associated with AS. Multiplex immunoassay profiling led to identification of 16 proteins that were significantly altered in AS individuals in a sex-specific manner. Three of these proteins were altered in females (ADIPO, IgA, APOA1), seven were changed in males (BMP6, CTGF, ICAM1, IL-12p70, IL-16, TF, TNF-alpha) and six were changed in both sexes but in opposite directions (CHGA, EPO, IL-3, TENA, PAP, SHBG). Shotgun LC-MSE profiling led to identification of 13 serum proteins which had significant sex-specific changes in the AS group and, of these, 12 were altered in females (APOC2, APOE, ARMC3, CLC4K, FETUB, GLCE, MRRP1, PTPA, RN149, TLE1, TRIPB, ZC3HE) and one protein was altered in males (RGPD4). The free androgen index in females with AS showed an increased ratio of 1.63 compared to controls.CONCLUSION:Taken together, the serum multiplex immunoassay and shotgun LC-MSE profiling results indicate that adult females with AS had alterations in proteins involved mostly in lipid transport and metabolism pathways, while adult males with AS showed changes predominantly in inflammation signalling. These results provide further evidence that the search for biomarkers or novel drug targets in AS may require stratification into male and female subgroups, and could lead to the development of novel targeted treatment approaches. En ligne : http://dx.doi.org/10.1186/2040-2392-5-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Synaptic vesicle dynamic changes in a model of fragile X / Jantine A.C. BROEK in Molecular Autism, 7 (2016)  

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