NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia

Bergman, Oded; Karry, Rachel; Milhem, Jumana; Ben‐Shachar, Dorit

doi:10.1038/s41380-018-0309-9

Cited by 27 publications

(18 citation statements)

References 76 publications

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“…The decreased expression of a number of mitochondria‐related genes was observed in postmortem brain tissues of patients with SCZ in smaller‐scale candidate gene‐based studies, including mitochondrial enzymes such as NADH: ubiquinone oxidoreductase core subunit V1(NDUFV1), NADH: ubiquinone oxidoreductase core subunit V2(NDUFV2), and NADH: ubiquinone oxidoreductase core subunit S1(NDUFS1) [ 35–37 ] and cytochrome c oxidase (COX) [ 38 ] in a brain region‐dependent manner. [ 35,36,38 ] In addition to the mitochondrial enzymes that mediate oxidative phosphorylation, the expression of a number of regulators of mitochondria such as NADH: ubiquinone oxidoreductase core subunit V2 pseudogene 1 (NDUFV2P1), a pseudogene that regulates the expression of NDUFV2, [ 39 ] and optic atrophy 1 (OPA1), [ 40,41 ] a regulator for mitochondrial fusion, was dysregulated in brain region‐dependent manner in SCZ.…”

Section: Mitochondria Dysfunction In People With Schizophreniamentioning

confidence: 99%

Mitochondrial Dysfunction in Schizophrenia

Chung

2020

BioEssays

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Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors. Accumulating evidence has pointed to the role of mitochondria and metabolic dysregulation in SCZ pathogenesis. This review critically summarizes recent studies associating a compromised mitochondrial function with people with SCZ, including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cell studies. This review also discusses animal models with mitochondrial dysfunction resulting in SCZ-relevant neurobehavioral abnormalities, as well as restoration of mitochondrial function as potential therapeutic targets. Further understanding of mitochondrial dysfunction in SCZ may open the door to develop novel therapeutic strategies that can address the symptoms that cannot be adequately addressed by current antipsychotics alone.

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Section: Mitochondria Dysfunction In People With Schizophreniamentioning

confidence: 99%

Mitochondrial Dysfunction in Schizophrenia

Chung

2020

BioEssays

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“…While the functional implications of this is difficult to determine due to the relative lack of understanding surrounding these non-coding genes, it should be noted that long non-coding RNAs have been observed to regulate gene expression at both the transcriptional and post-transcriptional levels, and have been implicated in various psychiatric disorders, such as SZ, ASD, MDD, and ID [93,94]. Similarly, pseudogene products have been recently shown to regulate gene expression [95], and their differential expression has been reported in several psychiatric disorders, including SZ [96]. It is therefore reasonable to speculate that their elevated expression may be a contributing factor to the large number of differentially expressed genes in the pre-treatment condition compared to cells exposed to oxidative stress during differentiation.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Impact on the Transcriptome of Differentiating Neuroblastoma Cells: Implication for Psychiatric Disorders

Khavari

Mahmoudi

Geaghan

et al. 2020

IJMS

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Prenatal environmental exposures that have been shown to induce oxidative stress (OS) during pregnancy, such as smoking and alcohol consumption, are risk factors for the onset of schizophrenia and other neurodevelopmental disorders (NDDs). While the OS role in the etiology of neurodegenerative diseases is well known, its contribution to the genomic dysregulation associated with psychiatric disorders is less well defined. In this study we used the SH-SY5Y cell line and applied RNA-sequencing to explore transcriptomic changes in response to OS before or during neural differentiation. We observed differential expression of many genes, most of which localised to the synapse and were involved in neuronal differentiation. These genes were enriched in schizophrenia-associated signalling pathways, including PI3K/Akt, axon guidance, and signalling by retinoic acid. Interestingly, circulatory system development was affected by both treatments, which is concordant with observations of increased prevalence of cardiovascular disease in patients with NDDs. We also observed a very significant increase in the expression of immunity-related genes, supporting current hypotheses of immune system involvement in psychiatric disorders. While further investigation of this influence in other cell and animal models is warranted, our data suggest that early life exposure to OS has a disruptive influence on neuronal gene expression that may perturb normal differentiation and neurodevelopment, thereby contributing towards overall risk for developing psychiatric diseases.

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“…The involved genes may be up-or down-regulated depending on a stage of disease [7]. Some recent studies on increased pseudogene expression in schizophrenia-derived cell lines showed that the NDUFV2P1 pseudogene contributes to mitochondrial complex I deficits [8]. In this study, we hypothesized that genetic analysis of schizophrenia may lead to clues to the evolutionary process of human and estimated possible selective pressures on specific nucleotides of samples from schizophrenic patients, using the RNU6-505P pseudogene as a marker for schizophrenia, with a focus on its postulated activity in the development of the human brain and involvement in different brain functions/diseases.…”

Section: Differential Expression Analysis On Schizophrenia Dataset Sumentioning

confidence: 99%

Differential Expression Analysis on Schizophrenia Dataset Suggests Pseudogene RNU6-505P as under Selective Pressure

2020

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Schizophrenia is one of the 15 leading causes of disability worldwide. About 1% of the global population has schizophrenia, with 10% of premature mortality chance. Schizophrenia is therefore associated with significant health, social and economic concerns. In this context, thalamus and striatum areas play important roles as much in schizophrenia as processing information before reaching the conscious thought: step happening soon in the creativity action. Creativity is defined by psychological scientists as the generation of ideas or products that are both original and valuable. Creativity relies on imagination and this fundamental human ability remains understudied in comparison to other important psychological phenomena. It is natural to ask whether the gene expression profiling of samples from schizophrenic patients could highlight the activity of some genes specific to humans. Microarray analysis of the dataset GSE25673 revealed that the pseudogene RNU6-505P is expressed differentially in schizophrenic samples and correlates to CYP26A1, ARHGAP18, TSPAN12, HEY2 and TMEM132A genes. Ontological analysis showed that the RNU6-505P pseudogene is involved in brain development and certain neurological pathologies. Evolutionary analysis showed that the AGA 3-nucleotide sequence of RNU6-505P has been under positive selective pressure. Finally, the 1-nucleotide mutation prediction test revealed that variations on the AGA nucleotides could be fatal to the RNA structure of the sequence. We conclude that differential expression of the RNU6-505P pseudogene can be valid to diagnose schizophrenia and the RNU6-505P pseudogene may have a relevant function in the cerebral development and in the divergent evolution of humans from apes.

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NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia

Cited by 27 publications

References 76 publications

Mitochondrial Dysfunction in Schizophrenia

Mitochondrial Dysfunction in Schizophrenia

Oxidative Stress Impact on the Transcriptome of Differentiating Neuroblastoma Cells: Implication for Psychiatric Disorders

Differential Expression Analysis on Schizophrenia Dataset Suggests Pseudogene RNU6-505P as under Selective Pressure

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