Mitochondrial complex i subunits expression is altered in schizophrenia: a postmortem study

Karry, Rachel; Klein, Ehud; Shachar, Dorit Ben

doi:10.1016/j.biopsych.2003.12.012

Cited by 187 publications

(159 citation statements)

References 66 publications

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“…Moreover, oligodendrocytes are an especially vulnerable cell population to many insults, and molecular abnormalities of oligodendrocytes are reported in association with many CNS disorders not involving myelin directly. A similar interpretational query affects another neuropathological theme that has emerged recently, that of mitochondrial and metabolic involvement in schizophrenia, for which there is also morphological, 103 biochemical, 104,105 and molecular 106,107 evidence. Additional conclusions regarding the post-mortem data are facilitated by consideration of imaging and other in vivo findings.…”

Section: Histological Findingsmentioning

confidence: 82%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. Molecular Psychiatry (2005) 10, 40-68.

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Section: Histological Findingsmentioning

confidence: 82%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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“…NCALD, also known as VSNL3, is a high-affinity Ca 2 þ sensor that has been found to interact with cytoskeletal proteins (Paterlini et al, 2000). In SCZ, evidence for brain mitochondrial dysfunction has been reported, including findings of impaired brain energy metabolism, developmental deviations, abnormal neurotransmission, and connectivity (Manji et al, 2012;Rosenfeld et al, 2011), along with mitochondrial hypoplasia, oxidative phosphorylation system imbalance, and altered mitochondrial protein expression (Karry et al, 2004;Prabakaran et al, 2004). Consistent with these reports, we detected alterations of several subunits of the electron transport chain complex I in the frontal cortex tissue from PCP-treated rats (NDUFA9, NDUFS3, NDUFV1, and NDUFV2).…”

Section: Biological Functions P-values Proteins Biological Functions mentioning

confidence: 99%

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Wesseling

Chan

Tsang

et al. 2013

Neuropsychopharmacol

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Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic-and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca 2 þ signaling (Ca 2 þ /calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca 2 þ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ.

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“…An in-vitro study by Burkhardt et al (1993) found that APs inhibited mitochondrial complex I. In addition, other studies found that injecting mice with different APs (HAL, CLZ and RIS) led to inhibition of complex I activity in different parts of the brain after a variable length of time ( Balijepalli et al, 2001;Karry et al,. 2004).…”

Section: Discussionmentioning

confidence: 99%

Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells

Elmorsy

Al‐Ghafari

Aggour³

et al. 2017

Toxicology Letters

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MANUSCRIPT: "Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells" Highlights: This study investigated the effects of four antipsychotics (APs) on mitochondrial bioenergetics and steroidogenesis of rats isolated ovarian theca interstitial cells (TICs) as a possible mechanism of reproductive toxicity. The APs used in this experiment include chlorpromazine (CPZ) haloperidol (HAL), risperidone (RIS) clozapine (CLZ).  All four APs seem to inhibit mitochondrial bioenergetics and steroidogenesis in rat's TICs.  These findings support the hypothesis that APs-induced reproductive toxicity may be through mechanisms involving mitochondrial insult. Abstract:Background: Antipsychotics (APs) are widely prescribed drugs, which are well known to cause

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Mitochondrial complex i subunits expression is altered in schizophrenia: a postmortem study

Cited by 187 publications

References 66 publications

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells

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