Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Pennington, Kyla; Beasley, Clare L.; Dicker, Patrick; Fagan, Ailís; English, James; Pariante, Carmine M.; Wait, Robin; Dünn, Michael J.; Cotter, David

doi:10.1038/sj.mp.4002098

Cited by 210 publications

(155 citation statements)

References 96 publications

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“…In addition, some approaches, such as chromatin-immunoprecipitation (ChIP), require large quantities of tissues from each subject (Huang et al, 2006). One approach to get around this issue has been pooling of samples; pooled samples are assayed and help generate specific hypotheses that may be tested with smaller quantities of tissue (English et al, 2009;English et al, 2011;Pennington et al, 2008). One area of postmortem proteomic research that lags behind transcript studies is the assessment of protein quality.…”

Section: Sample Quantity and Qualitymentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

107

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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Section: Sample Quantity and Qualitymentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

107

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“…It was decided that validation experiments should focus on the most interesting of these proteins. Building on our findings 14,17 and those of others 15,16 of synaptic changes in both SCZ and BPD, selection criteria for these were that (i) proteins demonstrated altered expression in both BPD and SCZ, and (ii) proteins were involved in synaptic and synaptic plasticityassociated functions. Proteins that met these criteria would be validated using western blotting in individual cases in an extended Stanley Foundation Array series with the validation then extended to the Harvard Brain Tissue Resource Centre McLean 66 brain series.…”

Section: Methodsmentioning

confidence: 99%

“…Most recently, our group undertook a proteomic analysis of the dlpfc 17 and further characterized the synaptic and synaptic-associated pathology in SCZ by demonstrating alterations in the septin family of proteins, protein kinase C and casein kinase in neurons 1 (PACSIN1) and neurofilament triplet L in SCZ. These findings complement the literature reporting changes in protein kinase C 18 and synaptic proteins 19 in SCZ, although some negative studies have been published.…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

et al. 2008

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The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n = 10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P < 0.001), BASP1 (40% difference; P < 0.05) and LAMP (22% difference; P < 0.01)) and BPD (STXBP1 (31% difference; P < 0.001), BASP1 (23% difference; P < 0.01) and LAMP (20% difference; P < 0.01)) in the Stanley brain series (n = 20 per group). Further validation in dlpfc from the Harvard brain subseries (n = 10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P < 0.0001), BASP1 (14% difference; P < 0.0001) but not LAMP (20% difference; P = 0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports the view of a neuritic and synaptic dysfunction in the neuropathology of SCZ.

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“…Cognitive dysfunction has also been observed in close relatives of schizophrenic (Snitz, MacDonald, & Carter, 2006) and bipolar disorder patients (Bora et al., 2009), further supporting the notion of a genetic component. Understanding how certain genetic vulnerabilities might affect or impair cognitive processes mediated by the prefrontal cortex (PFC) is of great importance given the functional abnormalities of the PFC present in schizophrenia and bipolar disorder (Pennington et al., 2008). Furthermore, the PFC appears to be particularly susceptible to early life stress.…”

Section: Introductionmentioning

confidence: 99%

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

et al. 2017

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IntroductionPrevious research has indicated that variation in genes encoding catechol‐O‐methyltransferase (COMT) and dopamine receptor D2 (DRD2) may influence cognitive function and that this may confer vulnerability to the development of mental health disorders such as schizophrenia. However, increasing evidence suggests environmental factors such as early life stress may interact with genetic variants in affecting these cognitive outcomes. This study investigated the effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress in healthy adults.MethodsOne hundred and twenty‐two healthy adult males (mean age 35.2 years, range 21–63) were enrolled in the study. Cognitive function was assessed using Cambridge Neuropsychological Test Automated Battery and early life stress was assessed using the Childhood Traumatic Events Scale (Pennebaker & Susman, 1988).Results DRD2 C957T was significantly associated with executive function, with CC homozygotes having significantly reduced performance in spatial working memory and spatial planning. A significant genotype–trauma interaction was found in Rapid Visual Information Processing test, a measure of sustained attention, with CC carriers who had experienced early life stress exhibiting impaired performance compared to the CC carriers without early life stressful experiences. There were no significant findings for COMT Val158Met.ConclusionsThis study supports previous findings that DRD2 C957T significantly affects performance on executive function related tasks in healthy individuals and shows for the first time that some of these effects may be mediated through the impact of childhood traumatic events. Future work should aim to clarify further the effect of stress on neuronal systems that are known to be vulnerable in mental health disorders and more specifically what the impact of this might be on cognitive function.

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Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Cited by 210 publications

References 96 publications

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

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