Melanie Foecking | Royal College of Surgeons in Ireland (original) (raw)

Papers by Melanie Foecking

Schizophrenia Research, Apr 1, 2010

Journal of Psychopharmacology, Jun 18, 2008

Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investiga... more Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investigations at the molecular level. Using two-dimensional gel electrophoresis, this study investigated similarities in protein expression between clomipramine, St John’s wort and a Chinese herbal formula, xiao-yao-san, often used in mood disorder treatment. HT22 cells, derived from a mouse hippocampal cell line, were treated for 24 h, and protein expression was compared with that of the untreated cells ( n = 4/group). Forty-three protein spots were found to be significantly differentially expressed ( P < 0.05) in more than one of the treatment groups. Twenty-nine of these were identified using mass spectrometry. The most affected proteins were those involved in the cytoskeleton and energy metabolism, and an up-regulation of vimentin by all three treatments was confirmed by Western blotting. This study provides preliminary evidence for multiple common molecular targets between conventional and alternative antidepressants, which appear to collectively affect neuronal plasticity.

PubMed, 2006

Multi-Western blots of more than 400 proteins were performed from brain extracts of mice submitte... more Multi-Western blots of more than 400 proteins were performed from brain extracts of mice submitted to transient focal ischemia induced by 1 h middle cerebral artery (MCA) thread occlusion. Measurements were carried out in groups of six animals in sham-operated controls, at the end of 1 h ischemia, and after 3 and 12 h recirculation. After MCA occlusion up to 45% of proteins were up- or downregulated in the ipsilateral hemisphere by a factor of 1.5 or more, as compared to sham-operated controls. The temporal regulation of several proteins in the ischemia-affected hemisphere after 1 h MCA thread occlusion is described. In the non-ischemic hemisphere the number of regulated proteins was close to 50%, indicating a hitherto unrecognized involvement of the opposite side. The proteomic approach of brain injury analysis goes beyond previous screenings of gene expression at the transcriptional level and although our study provides further evidence for the complexity of multiinjury pathways in the evolution of ischemic brain damage it may help to identify key mediators of ischemic injury.

Early Intervention in Psychiatry, Mar 2, 2021

Aim: Among different types of poly unsaturated fatty acids, omega-3 fatty acids (FA) play a subst... more Aim: Among different types of poly unsaturated fatty acids, omega-3 fatty acids (FA) play a substantial role in brain development and functioning. This review was designed to evaluate and synthesize available evidence regarding omega-3 FAs and functional outcome in the ultra-high-risk (UHR) population. Methods: An electronic search in PubMed, EMBASE, PSYCINFO and COCHRANE search engines has been performed for all articles published until January 2019. The studies that have data regarding omega-3 FAs and functional outcome in UHR population were included. Results: Out of 397 nonduplicate citations, 19 articles met selection criteria. These articles were from four different primary studies, namely the Program of Rehabilitation and Therapy (PORT), the North American Prodromal Longitudinal Studies (NAPLS), Vienna High Risk study (VHR) and the NEURAPRO. The data from the NAPLS study found a positive correlation between functional improvement and frequency of dietary intake omega-3 FA. Moreover, among the erythrocyte omega-3 FA only eicosapentaenoic acid (EPA) showed a positive correlation with functional score. The VHR study found longterm improvement in functional outcome in omega-3 group compared to control, whereas such difference was noticed in the NEURAPRO. In the VHR study both omega-3 and omega-6 together predicted the functional improvement at 12 weeks. Conclusions: The number of studies available remains insufficient and more studies with standardized outcome measures in a clinically comparable UHR population would be of more value to understand the clinical benefits of omega-3 FA in the UHR population.

Schizophrenia Research, Aug 1, 2020

Background: There is renewed focus on the complement system in the pathogenesis of schizophrenia.... more Background: There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma may have clinical utility as biomarkers. Methods: We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference [SMD]) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012). Results: Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval [CI]-0.29-0.36) and 10 studies of C4 (SMD 0.10, 95% CI-0.21-0.41). Conclusions: Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders.

Proteomics, Jun 1, 2009

The mechanisms underlying white matter changes in psychiatric disease are not known. We aimed to ... more The mechanisms underlying white matter changes in psychiatric disease are not known. We aimed to characterise the differential protein expression in deep white matter from the dorsolateral prefrontal cortex from 35 schizophrenia, 35 bipolar disorder, and 35 control subjects, from the Stanley Array Collection. We used 2‐D DIGE to profile for protein expression changes in the brain. We found 70 protein spots to be significantly differentially expressed between disease and control subjects (ANCOVA, p<0.05), 46 of which were subsequently identified by LC‐MS/MS. The proteins identified included novel disease candidates as well as proteins that have previously been reported as abnormal in schizophrenia, thus reinforcing their association with the disease. Furthermore, we confirmed the direction of change for three proteins using ELISA, namely neurofilament‐light, amphiphysin II, and Rab‐GDP‐α, in a subset of the Stanley Array Collection. In addition, altered expression of neurofilament‐light, amphiphysin II, and Rab‐GDP‐α was not observed in the cortex of mice chronically treated with haloperidol, making it less likely that these alterations are a consequence of neuroleptic medication. The data presented here strongly suggest disruption of the cytoskeleton and its associated signal transduction proteins in schizophrenia, and to a lesser extent in bipolar disorder.

Schizophrenia Research, Apr 1, 2012

Schizophrenia Research, Apr 1, 2012

bioRxiv (Cold Spring Harbor Laboratory), Aug 27, 2020

Schizophrenia is a heterogeneous disorder associated with many genetic and environmental risk fac... more Schizophrenia is a heterogeneous disorder associated with many genetic and environmental risk factors that could affect brain development. It is unknown whether adolescent-onset and adult-onset schizophrenia have similar aetiology. To address this we used discovery-based proteomics to find proteins differentially expressed in olfactory neurosphere-derived cells from adolescents with schizophrenia compared to age-and gender-matched healthy controls. Of 1638 proteins identified, 241 were differentially expressed in patient cells, with significant down-regulation of ribosomal and cytoskeletal proteins, and dysregulation of protein synthesis pathways. We then re-analysed our previous adult-onset proteomic data to compare directly with adolescent-onset protein expression. Schizophrenia-associated protein expression in adult-onset patients was remarkably similar to adolescent-onset patients. To increase sample size and power we combined the two datasets for a bioinformatic meta-analysis. Schizophreniaassociated protein expression indicated significant downregulation of the mTOR signalling pathway, which regulates protein synthesis, indicated by the reduced expression of all ribosomal proteins and other mTOR-dependent proteins: RPS6, VIM, LDHB and PPP2R1A. A protein-protein interaction network built from differentially expressed proteins in the combined dataset was significantly associated with schizophrenia-associated risk genes and with proteins regulating neural stem cell differentiation, cell adhesion and growth cones in the developing (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. brain. This study demonstrates that despite the divergent age of onset, the proteomes of olfactory neural stem cells of adolescent-and adult-onset patients are remarkably similar. The dysregulated proteins in patient cells form a tightly interconnected protein-protein interaction network associated with mTOR signalling, protein translation, neurogenesis and axon growth-all key components of brain development.

Schizophrenia Research, Apr 1, 2014

Schizophrenia Research, Jun 1, 2008

Methods: Dorsolateral prefrontal grey and white matter was obtained from the Stanley Medical Rese... more Methods: Dorsolateral prefrontal grey and white matter was obtained from the Stanley Medical Research Institute Brain Collection (schizophrenia, bipolar disorder and controls; all n=35). Cholesterol levels were quantified using HPLC with ELSD. DNA was extracted and ApoE genotyping performed using PCR-RFLP. Results: In grey matter, cholesterol levels were 10% and 6% lower in schizophrenia and bipolar disorder respectively, relative to the control group. In white matter cholesterol levels were unchanged in both disorders. Repeated measures ANOVA revealed an effect of region, but no significant effect of diagnosis or region by diagnosis interaction. Preliminary analyses of the first 60 cases indicate that overall e4 alleles are associated with lower cholesterol levels in white but not grey matter. Conclusions: We were not able to identify deficits in cholesterol in the dorsolateral prefrontal region in schizophrenia or bipolar disorder. ApoE genotype may influence regulation of brain cholesterol. References [1] Beasley CL et al (2005). Reductions in cholesterol and synaptic markers in association cortex in mood disorders. [2] Bipolar Disord. 7:449-455.

Advances in biological psychiatry, 2014

Proteomics offers the ability to monitor and identify changes in protein expression and/or signal... more Proteomics offers the ability to monitor and identify changes in protein expression and/or signalling pathways with high precision, accuracy and reproducibility. Proteomic techniques, including bioinformatics software, are steadily advancing, and technical improvements to the methods currently employed for protein separation and protein identification will dramatically increase the number of proteomics-based schizophrenia research studies. The advent of high-throughput techniques allows scientists to quantify complex biological mixtures, such as postmortem brain, and to identify and validate new biomarkers. Animal models have contributed much to our understanding of disease mechanisms and are often utilised in research because of their abundant supply and ease of manipulation. Different theories regarding the aetiology of schizophrenia make the design of a single schizophrenia animal model impossible. Therefore, there are many preclinical animal models for schizophrenia research, each of which has relevance to different aspects of the neurobiology of the disorder and its treatment. Preclinical animal models in schizophrenia research are vital for biomarker discovery and in the exploration of disease neurobiology. Furthermore they are central for the testing of new drugs. Animal models in this aspect have the advantage that they enable the investigation of the neurobiology of the phenomena of interest using invasive techniques that cannot be used in humans. Proteomics-based research of these preclinical models can greatly increase our understanding of schizophrenia and shape the direction of future research. Current proteomic studies have so far been insightful and point to a role for mitochondrial dysfunction, alteration in cell signalling and cytoskeletal functioning in preclinical models. Proteomic studies of antipsychotics in preclinical models are an indispensable tool for investigating underlying schizophrenia neurobiology. Current investigations have found alterations in core mitochondrial proteins and in protein synthesis and cell signalling pathways in preclinical models of schizophrenia undergoing antipsychotic treatment. Research is encouraging, and advancement with preclinical models of schizophrenia can be made with more reliable quantitative proteomic methods. Proteomic studies on preclinical models of schizophrenia are, to date, somewhat sparse, but will hopefully multiply with the establishment of better quantitative approaches.

Neuroscience Letters, 2004

Statins are lipid-lowering drugs that have been shown to reduce atherosclerotic cardiovascular mo... more Statins are lipid-lowering drugs that have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. However, there is growing evidence from epidemiological studies that long-term treatment with statins has unwanted effects on extrahepatic tissue and increases the risk for neuropathy. To investigate underlying molecular mechanisms we analyzed whether statins influence the activity of caspase-3 in immortalized neurons. Lovastatin and mevastatin are not able to activate caspase-3 but they strongly potentiate its activity when apoptotic signal transduction is initiated by staurosporine. The increase in caspase-3 activity after coincubation with statins and staurosporine was paralleled by an increase in the protein level of the pro-apoptotic GTPase RhoB. Our data provide evidence that statins enhance neuronal apoptosis and therefore give reasons for a careful evaluation when patients with neurological diseases are treated with these drugs.

Biological Psychiatry, Jul 1, 2019

BACKGROUND: The identification of early biomarkers of psychotic experiences (PEs) is of interest ... more BACKGROUND: The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. METHODS: Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects. RESULTS: Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p , .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles. CONCLUSIONS: Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.

Proteomics, Sep 1, 2006

Brain development and aging is a complex process involving proliferation, differentiation and apo... more Brain development and aging is a complex process involving proliferation, differentiation and apoptosis. Elucidating proteome changes in these processes can help to understand the mechanisms of brain development and maintenance as well as neurodegenerative diseases. The research reported here is a contribution to the HUPO Brain Proteome Project mouse pilot study. Whole, frozen C57BL/6J mouse brain comprising three different developmental stages (embryonic day 16, postnatal day 7, and postnatal days 54-58) were processed by using 2-D DIGE. A total of 1999 spots were matched between all gels. Of these, 206 spots were differentially expressed between the different stages: 122 spots were highest in intensity in embryonic stage E16, 26 highest in the juvenile group P7 and 58 spots highest in P56, the adult stage. The results show a pattern of temporal expression. Based on the expression patterns we tentatively suggest that proteins involved in the establishment of primary structures in the brain are expressed highest in the embryonic mouse. Proteins involved in the development of the brain are expressed highest in the juvenile phase and proteins that make utilization of the brain possible by delivering energy are expressed highest in the adult mice.

Schizophrenia Research, Apr 1, 2014

inflammatory changes in first psychotic episodes and their involvement in cognitive function. The... more inflammatory changes in first psychotic episodes and their involvement in cognitive function. The aim of this study is to determine the relationship between the anti-inflammatory mediator 15d-PGJ2 and premorbid intelligence in a sample of first episodes of psychosis (FEP). Methods: Case-control study of 92 FEP patients and 80 gender, race and age matched controls. All subjects were administered Vocabulary subtest for measures of IQ (WISC-IV Vocabulary in child and WAIS-III in adult). The anti-inflammatory mediator 15d-PGJ2 were measured in plasma. All patients were administered the PANSS for psychopathology. Results: A positive correlation is obtained between the anti-inflammatory mediator 15d-PGJ2 and measures of IQ (r=0.222; p=0.042) in patients sample. No correlation was found in healthy controls. Further analyses will be performed to evaluate the relationship between other inflammatory markers and cognition domains. Discussion: The anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis and can provide a better understanding of the physiological mechanisms involved in cognition. Because the high predictive power of cognition for psychosocial functional outcome, these results could allow early intervention to improve the prognosis and course of the condition.

Brain, Behavior, and Immunity

Brain, Behavior, and Immunity

Prenatal stress influences the development of the fetal brain and so contributes to the risk of t... more Prenatal stress influences the development of the fetal brain and so contributes to the risk of the development of psychiatric disorders in later life. The hippocampus is particularly sensitive to prenatal stress, and robust abnormalities have been described in the hippocampus in schizophrenia and depression. The aim of this study was to determine whether prenatal stress is associated with distinct patterns of differential protein expression in the hippocampus using a validated mouse model. We therefore performed a comparative proteomic study assessing female hippocampal samples from 8 prenatally stressed mice and 8 control mice. Differential protein expression was assessed using 2-dimensional difference in gel electrophoresis and subsequent mass spectrometry. The observed changes in a selected group of differentially expressed proteins were confirmed by Western blotting. In comparison to controls, 47 protein spots (38 individual proteins) were found to be differentially expressed i...

Schizophrenia Research, Apr 1, 2010

Journal of Psychopharmacology, Jun 18, 2008

Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investiga... more Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investigations at the molecular level. Using two-dimensional gel electrophoresis, this study investigated similarities in protein expression between clomipramine, St John’s wort and a Chinese herbal formula, xiao-yao-san, often used in mood disorder treatment. HT22 cells, derived from a mouse hippocampal cell line, were treated for 24 h, and protein expression was compared with that of the untreated cells ( n = 4/group). Forty-three protein spots were found to be significantly differentially expressed ( P < 0.05) in more than one of the treatment groups. Twenty-nine of these were identified using mass spectrometry. The most affected proteins were those involved in the cytoskeleton and energy metabolism, and an up-regulation of vimentin by all three treatments was confirmed by Western blotting. This study provides preliminary evidence for multiple common molecular targets between conventional and alternative antidepressants, which appear to collectively affect neuronal plasticity.

PubMed, 2006

Multi-Western blots of more than 400 proteins were performed from brain extracts of mice submitte... more Multi-Western blots of more than 400 proteins were performed from brain extracts of mice submitted to transient focal ischemia induced by 1 h middle cerebral artery (MCA) thread occlusion. Measurements were carried out in groups of six animals in sham-operated controls, at the end of 1 h ischemia, and after 3 and 12 h recirculation. After MCA occlusion up to 45% of proteins were up- or downregulated in the ipsilateral hemisphere by a factor of 1.5 or more, as compared to sham-operated controls. The temporal regulation of several proteins in the ischemia-affected hemisphere after 1 h MCA thread occlusion is described. In the non-ischemic hemisphere the number of regulated proteins was close to 50%, indicating a hitherto unrecognized involvement of the opposite side. The proteomic approach of brain injury analysis goes beyond previous screenings of gene expression at the transcriptional level and although our study provides further evidence for the complexity of multiinjury pathways in the evolution of ischemic brain damage it may help to identify key mediators of ischemic injury.

Early Intervention in Psychiatry, Mar 2, 2021

Aim: Among different types of poly unsaturated fatty acids, omega-3 fatty acids (FA) play a subst... more Aim: Among different types of poly unsaturated fatty acids, omega-3 fatty acids (FA) play a substantial role in brain development and functioning. This review was designed to evaluate and synthesize available evidence regarding omega-3 FAs and functional outcome in the ultra-high-risk (UHR) population. Methods: An electronic search in PubMed, EMBASE, PSYCINFO and COCHRANE search engines has been performed for all articles published until January 2019. The studies that have data regarding omega-3 FAs and functional outcome in UHR population were included. Results: Out of 397 nonduplicate citations, 19 articles met selection criteria. These articles were from four different primary studies, namely the Program of Rehabilitation and Therapy (PORT), the North American Prodromal Longitudinal Studies (NAPLS), Vienna High Risk study (VHR) and the NEURAPRO. The data from the NAPLS study found a positive correlation between functional improvement and frequency of dietary intake omega-3 FA. Moreover, among the erythrocyte omega-3 FA only eicosapentaenoic acid (EPA) showed a positive correlation with functional score. The VHR study found longterm improvement in functional outcome in omega-3 group compared to control, whereas such difference was noticed in the NEURAPRO. In the VHR study both omega-3 and omega-6 together predicted the functional improvement at 12 weeks. Conclusions: The number of studies available remains insufficient and more studies with standardized outcome measures in a clinically comparable UHR population would be of more value to understand the clinical benefits of omega-3 FA in the UHR population.

Schizophrenia Research, Aug 1, 2020

Background: There is renewed focus on the complement system in the pathogenesis of schizophrenia.... more Background: There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma may have clinical utility as biomarkers. Methods: We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference [SMD]) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012). Results: Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval [CI]-0.29-0.36) and 10 studies of C4 (SMD 0.10, 95% CI-0.21-0.41). Conclusions: Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders.

Proteomics, Jun 1, 2009

The mechanisms underlying white matter changes in psychiatric disease are not known. We aimed to ... more The mechanisms underlying white matter changes in psychiatric disease are not known. We aimed to characterise the differential protein expression in deep white matter from the dorsolateral prefrontal cortex from 35 schizophrenia, 35 bipolar disorder, and 35 control subjects, from the Stanley Array Collection. We used 2‐D DIGE to profile for protein expression changes in the brain. We found 70 protein spots to be significantly differentially expressed between disease and control subjects (ANCOVA, p<0.05), 46 of which were subsequently identified by LC‐MS/MS. The proteins identified included novel disease candidates as well as proteins that have previously been reported as abnormal in schizophrenia, thus reinforcing their association with the disease. Furthermore, we confirmed the direction of change for three proteins using ELISA, namely neurofilament‐light, amphiphysin II, and Rab‐GDP‐α, in a subset of the Stanley Array Collection. In addition, altered expression of neurofilament‐light, amphiphysin II, and Rab‐GDP‐α was not observed in the cortex of mice chronically treated with haloperidol, making it less likely that these alterations are a consequence of neuroleptic medication. The data presented here strongly suggest disruption of the cytoskeleton and its associated signal transduction proteins in schizophrenia, and to a lesser extent in bipolar disorder.

Schizophrenia Research, Apr 1, 2012

Schizophrenia Research, Apr 1, 2012

bioRxiv (Cold Spring Harbor Laboratory), Aug 27, 2020

Schizophrenia is a heterogeneous disorder associated with many genetic and environmental risk fac... more Schizophrenia is a heterogeneous disorder associated with many genetic and environmental risk factors that could affect brain development. It is unknown whether adolescent-onset and adult-onset schizophrenia have similar aetiology. To address this we used discovery-based proteomics to find proteins differentially expressed in olfactory neurosphere-derived cells from adolescents with schizophrenia compared to age-and gender-matched healthy controls. Of 1638 proteins identified, 241 were differentially expressed in patient cells, with significant down-regulation of ribosomal and cytoskeletal proteins, and dysregulation of protein synthesis pathways. We then re-analysed our previous adult-onset proteomic data to compare directly with adolescent-onset protein expression. Schizophrenia-associated protein expression in adult-onset patients was remarkably similar to adolescent-onset patients. To increase sample size and power we combined the two datasets for a bioinformatic meta-analysis. Schizophreniaassociated protein expression indicated significant downregulation of the mTOR signalling pathway, which regulates protein synthesis, indicated by the reduced expression of all ribosomal proteins and other mTOR-dependent proteins: RPS6, VIM, LDHB and PPP2R1A. A protein-protein interaction network built from differentially expressed proteins in the combined dataset was significantly associated with schizophrenia-associated risk genes and with proteins regulating neural stem cell differentiation, cell adhesion and growth cones in the developing (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. brain. This study demonstrates that despite the divergent age of onset, the proteomes of olfactory neural stem cells of adolescent-and adult-onset patients are remarkably similar. The dysregulated proteins in patient cells form a tightly interconnected protein-protein interaction network associated with mTOR signalling, protein translation, neurogenesis and axon growth-all key components of brain development.

Schizophrenia Research, Apr 1, 2014

Schizophrenia Research, Jun 1, 2008

Methods: Dorsolateral prefrontal grey and white matter was obtained from the Stanley Medical Rese... more Methods: Dorsolateral prefrontal grey and white matter was obtained from the Stanley Medical Research Institute Brain Collection (schizophrenia, bipolar disorder and controls; all n=35). Cholesterol levels were quantified using HPLC with ELSD. DNA was extracted and ApoE genotyping performed using PCR-RFLP. Results: In grey matter, cholesterol levels were 10% and 6% lower in schizophrenia and bipolar disorder respectively, relative to the control group. In white matter cholesterol levels were unchanged in both disorders. Repeated measures ANOVA revealed an effect of region, but no significant effect of diagnosis or region by diagnosis interaction. Preliminary analyses of the first 60 cases indicate that overall e4 alleles are associated with lower cholesterol levels in white but not grey matter. Conclusions: We were not able to identify deficits in cholesterol in the dorsolateral prefrontal region in schizophrenia or bipolar disorder. ApoE genotype may influence regulation of brain cholesterol. References [1] Beasley CL et al (2005). Reductions in cholesterol and synaptic markers in association cortex in mood disorders. [2] Bipolar Disord. 7:449-455.

Advances in biological psychiatry, 2014

Proteomics offers the ability to monitor and identify changes in protein expression and/or signal... more Proteomics offers the ability to monitor and identify changes in protein expression and/or signalling pathways with high precision, accuracy and reproducibility. Proteomic techniques, including bioinformatics software, are steadily advancing, and technical improvements to the methods currently employed for protein separation and protein identification will dramatically increase the number of proteomics-based schizophrenia research studies. The advent of high-throughput techniques allows scientists to quantify complex biological mixtures, such as postmortem brain, and to identify and validate new biomarkers. Animal models have contributed much to our understanding of disease mechanisms and are often utilised in research because of their abundant supply and ease of manipulation. Different theories regarding the aetiology of schizophrenia make the design of a single schizophrenia animal model impossible. Therefore, there are many preclinical animal models for schizophrenia research, each of which has relevance to different aspects of the neurobiology of the disorder and its treatment. Preclinical animal models in schizophrenia research are vital for biomarker discovery and in the exploration of disease neurobiology. Furthermore they are central for the testing of new drugs. Animal models in this aspect have the advantage that they enable the investigation of the neurobiology of the phenomena of interest using invasive techniques that cannot be used in humans. Proteomics-based research of these preclinical models can greatly increase our understanding of schizophrenia and shape the direction of future research. Current proteomic studies have so far been insightful and point to a role for mitochondrial dysfunction, alteration in cell signalling and cytoskeletal functioning in preclinical models. Proteomic studies of antipsychotics in preclinical models are an indispensable tool for investigating underlying schizophrenia neurobiology. Current investigations have found alterations in core mitochondrial proteins and in protein synthesis and cell signalling pathways in preclinical models of schizophrenia undergoing antipsychotic treatment. Research is encouraging, and advancement with preclinical models of schizophrenia can be made with more reliable quantitative proteomic methods. Proteomic studies on preclinical models of schizophrenia are, to date, somewhat sparse, but will hopefully multiply with the establishment of better quantitative approaches.

Neuroscience Letters, 2004

Statins are lipid-lowering drugs that have been shown to reduce atherosclerotic cardiovascular mo... more Statins are lipid-lowering drugs that have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. However, there is growing evidence from epidemiological studies that long-term treatment with statins has unwanted effects on extrahepatic tissue and increases the risk for neuropathy. To investigate underlying molecular mechanisms we analyzed whether statins influence the activity of caspase-3 in immortalized neurons. Lovastatin and mevastatin are not able to activate caspase-3 but they strongly potentiate its activity when apoptotic signal transduction is initiated by staurosporine. The increase in caspase-3 activity after coincubation with statins and staurosporine was paralleled by an increase in the protein level of the pro-apoptotic GTPase RhoB. Our data provide evidence that statins enhance neuronal apoptosis and therefore give reasons for a careful evaluation when patients with neurological diseases are treated with these drugs.

Biological Psychiatry, Jul 1, 2019

BACKGROUND: The identification of early biomarkers of psychotic experiences (PEs) is of interest ... more BACKGROUND: The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. METHODS: Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects. RESULTS: Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p , .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles. CONCLUSIONS: Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.

Proteomics, Sep 1, 2006

Brain development and aging is a complex process involving proliferation, differentiation and apo... more Brain development and aging is a complex process involving proliferation, differentiation and apoptosis. Elucidating proteome changes in these processes can help to understand the mechanisms of brain development and maintenance as well as neurodegenerative diseases. The research reported here is a contribution to the HUPO Brain Proteome Project mouse pilot study. Whole, frozen C57BL/6J mouse brain comprising three different developmental stages (embryonic day 16, postnatal day 7, and postnatal days 54-58) were processed by using 2-D DIGE. A total of 1999 spots were matched between all gels. Of these, 206 spots were differentially expressed between the different stages: 122 spots were highest in intensity in embryonic stage E16, 26 highest in the juvenile group P7 and 58 spots highest in P56, the adult stage. The results show a pattern of temporal expression. Based on the expression patterns we tentatively suggest that proteins involved in the establishment of primary structures in the brain are expressed highest in the embryonic mouse. Proteins involved in the development of the brain are expressed highest in the juvenile phase and proteins that make utilization of the brain possible by delivering energy are expressed highest in the adult mice.

Schizophrenia Research, Apr 1, 2014

inflammatory changes in first psychotic episodes and their involvement in cognitive function. The... more inflammatory changes in first psychotic episodes and their involvement in cognitive function. The aim of this study is to determine the relationship between the anti-inflammatory mediator 15d-PGJ2 and premorbid intelligence in a sample of first episodes of psychosis (FEP). Methods: Case-control study of 92 FEP patients and 80 gender, race and age matched controls. All subjects were administered Vocabulary subtest for measures of IQ (WISC-IV Vocabulary in child and WAIS-III in adult). The anti-inflammatory mediator 15d-PGJ2 were measured in plasma. All patients were administered the PANSS for psychopathology. Results: A positive correlation is obtained between the anti-inflammatory mediator 15d-PGJ2 and measures of IQ (r=0.222; p=0.042) in patients sample. No correlation was found in healthy controls. Further analyses will be performed to evaluate the relationship between other inflammatory markers and cognition domains. Discussion: The anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis and can provide a better understanding of the physiological mechanisms involved in cognition. Because the high predictive power of cognition for psychosocial functional outcome, these results could allow early intervention to improve the prognosis and course of the condition.

Brain, Behavior, and Immunity

Brain, Behavior, and Immunity

Prenatal stress influences the development of the fetal brain and so contributes to the risk of t... more Prenatal stress influences the development of the fetal brain and so contributes to the risk of the development of psychiatric disorders in later life. The hippocampus is particularly sensitive to prenatal stress, and robust abnormalities have been described in the hippocampus in schizophrenia and depression. The aim of this study was to determine whether prenatal stress is associated with distinct patterns of differential protein expression in the hippocampus using a validated mouse model. We therefore performed a comparative proteomic study assessing female hippocampal samples from 8 prenatally stressed mice and 8 control mice. Differential protein expression was assessed using 2-dimensional difference in gel electrophoresis and subsequent mass spectrometry. The observed changes in a selected group of differentially expressed proteins were confirmed by Western blotting. In comparison to controls, 47 protein spots (38 individual proteins) were found to be differentially expressed i...