Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Prabakaran, Sudhakaran; Swatton, Jane E.; Ryan, Margaret M.; Huffaker, Stephen J.; Huang, Jeffrey T.‐J.; Griffin, Julian L.; Wayland, Matthew T.; Freeman, Tom P; Dudbridge, Frank; Lilley, Kathryn S.; Karp, Natasha A.; Hester, Svenja; Tkachev, Dmitri; Mimmack, Michael L.; Yolken, Robert H.; Webster, Maree J.; Torrey, Ε. Fuller; Bahn, Sabine

doi:10.1038/sj.mp.4001511

Cited by 727 publications

(561 citation statements)

References 67 publications

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“…Several postmortem studies in schizophrenia have demonstrated reduced expression of oligodendrocyte-related genes, [17][18][19][20][21][67][68][69][70][71][72] some of which may be susceptibility genes for schizophrenia. 33,[72][73][74][75] Moreover, several studies have evidence for deficits in oligodendrocytes in the disorder.…”

Section: Discussionmentioning

confidence: 99%

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

et al. 2007

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Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase b/f (RPTPb), we postulated that simultaneous binding of MAGI proteins to RPTPb and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPb. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPb for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n = B1400). PTPRZ1, which codes for RPTPb, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P = 0.0003; gene-wide P = 0.0064; hypothesiswide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTPb signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPb in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

et al. 2007

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“…Data from the schizophrenia analysis have been previously published, and none of the findings in bipolar disorder described here were found in the schizophrenia samples. 16 Both gray and white matter bipolar tissue were separated well from the corresponding control tissue based on PLS-DA models (Figures 1b and c). A number of metabolites were found to contribute to this separation including myo-inositol, glutamate, lactate, phosphocholine and creatine ( Figure 1a; Table 2).…”

Section: Post-mortem Brain Tissue Analysismentioning

confidence: 92%

“…Although there are many platforms for metabolic profiling (for example, LC-MS, GC-MS, NMR, electrocapillary phoresis-MS), no one technology gives complete coverage of the metabonome. This technique has been used extensively in studies on schizophrenia, [16][17][18][19] Alzheimer's disease, 20 Huntington's disease, 21 Batten disease 22 and human brain tumors 23 (for detailed reviews on metabonomics, see Holmes et al 24 and Lenz and Wilson 25 ). These studies have identified a number of biochemical alterations that may be occurring as part of the pathogenesis of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

et al. 2008

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Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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“…These are fructose bisphosphate aldolase C (FBA-C, absent in schizophrenia), citrate synthase (absent in schizophrenia), two spots corresponding to isocitrate dehydrogenase (À1.692 and absent), and NADH ubiquinine oxidoreductase (À1.944). FBA-C, a glycolytic enzyme, has previously been implicated in schizophrenia with increased levels in the frontal cortex proteome of schizophrenia patients, 19 reduced levels in both the gray and white matter of the PFC proteome 18 and an increased immunoreactivity in schizophrenia CSF. 33 Citrate synthase and isocitrate dehydrogenase form a part of the citric acid cycle.…”

Section: Metabolismmentioning

confidence: 99%

“…Proteomics, with the ability to investigate the translation of genomic information together with co-and post-translational modifications, 17 offers an approach to studying the global changes in protein expression and modification caused by neuropathologies such as Alzheimer's Disease (AD), Down Syndrome (DS) and schizophrenia. Previous findings of proteomic investigations into schizophrenia include various proteins associated with metabolism and oxidative stress to be differentially expressed in the prefrontal cortex (PFC) in the disease state relative to controls, 18 proteins previously implicated in schizophrenia as well as some novel proteins to be altered in the frontal cortex, 19 and four of 18 altered proteins in the schizophrenia hippocampus mapping to chromosome 6q. 20 In addition, a proteomic study investigating the cerebrospinal fluid (CSF) in schizophrenia identified 54 different gene products, 17 leading to new and refined hypotheses into the molecular mechanisms underlying this disease.…”

Section: Introductionmentioning

confidence: 99%

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

et al. 2006

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The Anterior Cingulate Cortex (ACC, Brodmans Area 24) is implicated in the pathogenesis of schizophrenia due to its normal functions and connectivity together with reports of structural, morphological and neurotransmitter aberrations within this brain area in the disease state. Two-dimensional gel electrophoresis (2DE) was employed to scan and compare the ACC gray matter proteomes between schizophrenia (n = 10) and control (n = 10) post-mortem human tissue. This proteomic approach has detected 42 protein spots with altered levels in the schizophrenia cohort, which to our knowledge is the first proteomic analysis of the ACC in schizophrenia. Thirty nine of these proteins were subsequently identified using mass spectrometry and functionally classified into metabolism and oxidative stress, cytoskeletal, synaptic, signalling, trafficking and glial-specific groups. Some of the identified proteins have previously been implicated in the disease pathogenesis and some offer new insights into schizophrenia. Investigating these proteins, the genes encoding these proteins, their functions and interactions may shed light on the molecular mechanisms underlying the heterogeneous symptoms characteristic of schizophrenia.

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Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Cited by 727 publications

References 67 publications

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

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