The role of oligodendrocyte pathology in schizophrenia

Na, Uranova; Vostrikov, V. M.; Vikhreva, Olga; Zimina, I.S.; Kolomeets, Natalya S.; Orlovskaya, D.D.

doi:10.1017/s1461145707007626

Cited by 153 publications

(103 citation statements)

References 55 publications

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“…35 However, there was no significant association between the cis SNPs and the expression level of the gene in the SNPExpress database, 24 and we were unable to confirm the SNP association in our samples, as the gene is absent from our expression microarray data set. Nevertheless, deficits in oligodendrocytes have been identified as a significant neuropathology in schizophrenia and in bipolar disorder, 36,37 and genome-wide expression profiling revealed that oligodendrocyte-related genes are downregulated in the PFC of both schizophrenia and bipolar disorder. [38][39][40] The findings from the genome-wide scan will need to be replicated by an independent association study with a larger sample size; however, the preliminary findings support the hypothesis that developmental deficits of oligodendrocytes may contribute to the etiology of major psychiatric disorders such as schizophrenia and bipolar disorder.…”

Section: Discussionmentioning

confidence: 99%

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

Kim

Webster

2010

Mol Psychiatry

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Cytoarchitectural abnormalities have been described in the prefrontal cortex (PFC) of subjects with psychiatric disorders. We explored the possible genetic causalities that may underlie the cytoarchitectural abnormalities of calbindin-containing c-aminobutyric acid (GABA)ergic neurons and perineuronal oligodendrocytes in the PFC of subjects with psychiatric disorders by converging results from genome-wide single-nucleotide polymorphism (SNP) scans for the traits and expression SNP (eSNP) associations. In the initial genome-wide scans, we identified several development-and apoptosis-related genes associated with the cytoarchitectural traits. Moreover, the susceptibility gene for bipolar disorder, PPP2R2C, was found to be associated with the number of perineuronal oligodendrocytes. Further eSNP analyses indicated that two novel candidate genes, RAB2A and SLC38A1, were associated with the density of calbindinpositive neurons and the number of perineuronal oligodendrocytes, respectively. Our findings may provide novel insights into the genetic causalities associated with cytoarchitectural abnormalities in the PFC of subjects with major psychiatric disorders as well as into the etiology of such disorders.

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Section: Discussionmentioning

confidence: 99%

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

Kim

Webster

2010

Mol Psychiatry

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“…Postmortem examination of schizophrenic brains has demonstrated structural abnormalities in both myelin sheaths and oligodendroglia and it has been hypothesized that oligodendroglial dysfunction induces abnormalities in myelin, thereby contributing to the disease etiology. [46][47][48] Alternatively, aberrant PI levels may influence vesicle trafficking and vesicle cycling, important determinants in neurotransmitter cycling. Hence, PI kinase genes (including PIK4CA, PIP5K2A and PIK3C2G) are functional candidates for contributing to the risk of developing schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

et al. 2007

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Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P = 6.1 Â 10 À6 ). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed Pp0.01). Our approach-of screening genes involved in a particular pathway for association-resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.

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“…125 While many questions remain regarding the involvement of white matter loss in schizophrenia, OL apoptosis has been reported in schizophrenic brains. 126 It remains to be seen whether this is a cause or consequence of schizophrenia. 127 …”

Section: Ols and Diseasementioning

confidence: 99%

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

2008

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Apoptosis plays a crucial role in brain development by ensuring that only appropriately growing, migrating, and synapse-forming neurons and their associated glial cells survive. This process involves an intimate relationship between cell-cell interactions and developmental cues and is further impacted by environmental stress during neurogenesis and disease. Oligodendrocytes (OLs), the major myelin-forming cells in the central nervous system, largely form after this wave of neurogenesis but also show a selective vulnerability to cell death stimuli depending on their stage of development. This can affect not only embryonic and early postnatal brain formation but also the response to demyelinating pathologies. In the present review, we discuss the stagespecific sensitivity of OL lineage cells to damage-induced death and how this might impact myelin survival and regeneration during injury or disease. Apoptosis is a major form of programmed cell death required for the normal development of metazoan tissues, including the brain. 1 During embryonic development of the brain, many more cells than ultimately needed are generated and then selection occurs, resulting in the apoptotic depletion of the surplus cells. The importance of the apoptotic pathway in early brain development has been demonstrated by the targeted deletion in mice of the death-specific cysteine proteases caspase-3 or caspase-9, or of the co-activator Apaf-1, all of which cause severe brain overgrowth and perinatal death. 2,3 In the adult brain, 90% of the cells belong to the glial lineage, which includes oligodendrocytes (OLs), astrocytes and microglia. The glia ensures proper development, function and repair of the neuronal network. This is possible through continuous cross-talk between the glia and neurons mediated by neurotransmitters, cytokines, growth and trophic factor secretion and signaling in a reciprocal manner. [4][5][6][7] In the central nervous system (CNS), OLs are responsible for axon myelination, which insulates the electrical signals transmitted between neurons. OL and neuron development is tightly regulated and the myelin sheath is constructed only when OLs reach maturity and neurons have grown appropriately. In response to injury or during the course of neurological diseases, the neuron-glia network can be replenished to some extent but the degree of repair is dependent on the developmental stage of the OL. This complexity is compounded by the differential sensitivity of OL lineage cells to apoptotic stimuli. In the present review, we will first briefly examine the stages of differentiation of OL cells and then discuss several diseases that are impacted by OL apoptosis, noting how the stage of cell differentiation governs the sensitivity to apoptosis. Defined Stages of OL DevelopmentOligodendrocyte development can be divided into four distinct stages according to the temporal expression of cell surface markers and morphology (Table 1). 8 In the first stage, OL progenitor cells (OPCs) originate from the neuroepithelium of the ventricul...

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The role of oligodendrocyte pathology in schizophrenia

Cited by 153 publications

References 55 publications

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

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