Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia

Föcking, Melanie; Lopez, Lorna M.; English, James; Dicker, Patrick; Wolff, Amy R.; Brindley, Elizabeth; Wynne, Kieran; Cagney, Gerard; Cotter, David

doi:10.1038/mp.2014.63

Cited by 151 publications

(146 citation statements)

References 70 publications

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“…Our study and another two studies (Table 3) also found another protein related to oxidative stress, peroxiredoxin-1 (PRDX1), to be downregulated, reinforcing the concept of a reduced response to oxidative stress [58,59].…”

Section: Resultssupporting

confidence: 60%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter-hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography-mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies.

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Section: Resultssupporting

confidence: 60%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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“…Several studies describe changes in the expression of genes functionally implicated in both pre-or post-synaptic mechanisms in schizophrenia patients 33,48,49 . Wen et al (2014) 49 have proposed a model in which large-scale transcriptional dysregulation in human neurons harboring alterations in disrupted in schizophrenia 1 (DISC1) could affect synaptic function and lead to major psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity

Siegert

Seo

Kwon

et al. 2017

European Neuropsychopharmacology

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Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genomewide significance level. However, the functional consequence of these risk alleles is unknown. Here, we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms (SNPs) in MIR137, and observed increased MIR137 levels compared to major allele-carrying cells. We found that miR-137 gain-of-function causes downregulation of the presynaptic target genes, Complexin-1 (Cplx1), Nsf, and Synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain-of-function results in changes in synaptic vesicle pool distribution, impaired mossy fiber-LTP induction and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.

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“…Because previous gene expression studies assessed biological functionality of schizophrenia-associated genes using pathway analyses (6)(7)(8), we investigated the current gene set of preferentially fetally expressed genes at a fetal effect threshold of .5 (n = 79 genes) using the GOstats R package (9), but we found no statistically significant enrichment for gene ontology terms in the current analysis. It is perhaps relevant that in the recent genome-wide association study that identified the 108 loci surveyed in this report, significant enrichment of GO terms also was not reported for the entire gene set.…”

mentioning

confidence: 99%

Investigation of the Prenatal Expression Patterns of 108 Schizophrenia-Associated Genetic Loci

Birnbaum

Jaffe

Chen

et al. 2015

Biological Psychiatry

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Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia

Cited by 151 publications

References 70 publications

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity

Investigation of the Prenatal Expression Patterns of 108 Schizophrenia-Associated Genetic Loci

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