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Chen H, Li S, Gu Y, Liang K, Li Y, Cheng B, Jiang Z, Hu X, Wang J, Wang T, Wang Q, Wan C, Sun Q, Zhou J, Guo H, Wang X. Blunted niacin skin flushing response in violent offenders with schizophrenia: A potential auxiliary diagnostic biomarker. J Psychiatr Res 2025; 184:249-255. [PMID: 40058163 DOI: 10.1016/j.jpsychires.2025.02.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/17/2025] [Accepted: 02/27/2025] [Indexed: 04/09/2025]
Abstract
Schizophrenia (SZ) is associated with an increased risk of violence, with clinical diagnosis primarily relies on symptomatology. The niacin skin flushing response (NSFR) is proposed as a potential biomarker for SZ, but its effectiveness in violent offenders with schizophrenia (VOSZ) remains unevaluated. This study investigates whether the diagnostic model differentiating general SZ patients (GSZ) from healthy controls (HCs) using NSFR can also distinguish VOSZ from HCs. SZ patients were continuously sampled based on the International Classification of Diseases, 10th Edition, and categorized into VOSZ (with a history of violent crimes), and GSZ (without such history). HCs had no psychiatric illnesses or violent crime history. A total of 315 VOSZ, 296 GSZ, and 281 HCs were recruited. Least absolute shrinkage and selection operator regression was used to select variables and construct diagnostic models based on NSFR. No significant differences in age, sex or BMI were observed among groups. Both VOSZ and GSZ exhibited similar blunted NSFR compared to HCs. The diagnostic model constructed by 14 NSFR variables distinguishing GSZ from HCs was successfully transferred to distinguish VOSZ from HCs, with areas under the curve of 0.796 (specificity = 81.6%, sensitivity = 64.2%) and 0.798 (specificity = 80.0%, sensitivity = 70.2%), respectively. Moreover, NSFR was unrelated to illness severity, violence, or antipsychotic dosage in VOSZ, suggesting it is a trait indicator of SZ. This study supports the NSFR as an objective diagnostic biomarker for distinguishing VOSZ from HCs, expanding its applicability, although it may not specifically identify violent offenders among SZ patients.
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Affiliation(s)
- Hui Chen
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Shuhui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Yu Gu
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Kai Liang
- The Forensic Psychiatric Hospital of Hunan, China
| | - Yingxu Li
- The Forensic Psychiatric Hospital of Hunan, China
| | - Bohao Cheng
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Zhengqian Jiang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Jinfeng Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Tianqi Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Qian Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Qiaoling Sun
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Jiansong Zhou
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Huijuan Guo
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
| | - Xiaoping Wang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
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Giménez-Palomo A, Dodd S, Anmella G, Carvalho AF, Scaini G, Quevedo J, Pacchiarotti I, Vieta E, Berk M. The Role of Mitochondria in Mood Disorders: From Physiology to Pathophysiology and to Treatment. Front Psychiatry 2021; 12:546801. [PMID: 34295268 PMCID: PMC8291901 DOI: 10.3389/fpsyt.2021.546801] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 05/24/2021] [Indexed: 12/30/2022] Open
Abstract
Mitochondria are cellular organelles involved in several biological processes, especially in energy production. Several studies have found a relationship between mitochondrial dysfunction and mood disorders, such as major depressive disorder and bipolar disorder. Impairments in energy production are found in these disorders together with higher levels of oxidative stress. Recently, many agents capable of enhancing antioxidant defenses or mitochondrial functioning have been studied for the treatment of mood disorders as adjuvant therapy to current pharmacological treatments. A better knowledge of mitochondrial physiology and pathophysiology might allow the identification of new therapeutic targets and the development and study of novel effective therapies to treat these specific mitochondrial impairments. This could be especially beneficial for treatment-resistant patients. In this article, we provide a focused narrative review of the currently available evidence supporting the involvement of mitochondrial dysfunction in mood disorders, the effects of current therapies on mitochondrial functions, and novel targeted therapies acting on mitochondrial pathways that might be useful for the treatment of mood disorders.
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Affiliation(s)
- Anna Giménez-Palomo
- Bipolar and Depressives Disorders Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Mental Health Research Networking Center (CIBERSAM), Madrid, Spain
| | - Seetal Dodd
- Deakin University, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, VIC, Australia.,Department of Psychiatry, Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Gerard Anmella
- Bipolar and Depressives Disorders Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Mental Health Research Networking Center (CIBERSAM), Madrid, Spain
| | - Andre F Carvalho
- Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Giselli Scaini
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Joao Quevedo
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States.,Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, Brazil.,Center of Excellence in Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Isabella Pacchiarotti
- Bipolar and Depressives Disorders Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Mental Health Research Networking Center (CIBERSAM), Madrid, Spain
| | - Eduard Vieta
- Bipolar and Depressives Disorders Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Mental Health Research Networking Center (CIBERSAM), Madrid, Spain
| | - Michael Berk
- School of Medicine, The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Barwon Health, Geelong, VIC, Australia.,Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia.,Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia
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Haghighatfard A, Andalib S, Amini Faskhodi M, Sadeghi S, Ghaderi AH, Moradkhani S, Rostampour J, Tabrizi Z, Mahmoodi A, Karimi T, Ghadimi Z. Gene expression study of mitochondrial complex I in schizophrenia and paranoid personality disorder. World J Biol Psychiatry 2019. [PMID: 28635542 DOI: 10.1080/15622975.2017.1282171] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The aetiology and molecular mechanisms of schizophrenia (SCZ) and paranoid personality disorder (PPD) are not yet clarified. The present study aimed to assess the role of mitochondrial complex I and cell bioenergetic pathways in the aetiology and characteristics of SCZ and PPD. METHODS mRNA levels of all genomic and mitochondrial genes which encode mitochondrial complex I subunits (44 genes) were assessed in blood in 634 SCZ, 340 PPD patients and 528 non-psychiatric subjects using quantitative real-time PCR, and associated comprehensive psychiatric, neurological and biochemical assessments. RESULTS Significant expression changes of 18 genes in SCZ patients and 11 genes in PPD patients were detected in mitochondrial complex I. Most of these genes were novel candidate genes for SCZ and PPD. Several correlations between mRNA levels and severity of symptoms, drug response, deficits in attention, working memory, executive functions and brain activities were found. CONCLUSIONS Deregulations of both core and supernumerary subunits of complex I are involved in the aetiology of SCZ and PPD. These deregulations have effects on brain activity as well as disorder characteristics.
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Affiliation(s)
- Arvin Haghighatfard
- a Department of Biology, Science and Research Branch , Islamic Azad University , Tehran , Iran
| | - Sarah Andalib
- b Institute for Brain and Cognitive Science , Shahid Beheshti University , Tehran , Iran
| | - Mozhdeh Amini Faskhodi
- c Department of Biology , Tehran Medical Branch, Islamic Azad University , Tehran , Iran
| | - Soha Sadeghi
- d Laboratory of Medical Genetics , National Institute of Genetic Engineering and Biotechnology (NIGEB) , Tehran , Iran
| | - Amir Hossein Ghaderi
- e Cognitive Neuroscience Lab, Department of Psychology , University of Tabriz , Tabriz , Iran
| | - Shadi Moradkhani
- f Department of Physics , Amirkabir University of Technology , Tehran , Iran
| | - Jalal Rostampour
- g Department of Cell & Molecular Biology , School of Biology, College of Science, University of Tehran , Tehran , Iran
| | - Zeinab Tabrizi
- h Department of Medical Immunology , Shahid Sadoughi University of Medical Sciences and Health Services , Yazd , Iran
| | - Ali Mahmoodi
- a Department of Biology, Science and Research Branch , Islamic Azad University , Tehran , Iran
| | - Talie Karimi
- i Medical Biotechnology Research Center, Ashkezar Branch , Islamic Azad University , Ashkezar , Iran
| | - Zakieh Ghadimi
- j Department of Biology , Qom Branch, Islamic Azad University , Qom , Iran
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Holper L, Ben-Shachar D, Mann JJ. Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease. Neuropsychopharmacology 2019; 44:837-849. [PMID: 29855563 PMCID: PMC6461987 DOI: 10.1038/s41386-018-0090-0] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/26/2018] [Accepted: 05/07/2018] [Indexed: 12/17/2022]
Abstract
Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.
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Affiliation(s)
- L Holper
- Division of Molecular Imaging and Neuropathology, Columbia University and New York State Psychiatric Institute, New York, NY, USA.
| | - D Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel
| | - J J Mann
- Division of Molecular Imaging and Neuropathology, Columbia University and New York State Psychiatric Institute, New York, NY, USA
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Diagnostic value of blood-derived microRNAs for schizophrenia: results of a meta-analysis and validation. Sci Rep 2017; 7:15328. [PMID: 29127368 PMCID: PMC5681644 DOI: 10.1038/s41598-017-15751-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 11/01/2017] [Indexed: 12/31/2022] Open
Abstract
There is an increasing interest in searching biomarkers for schizophrenia (SZ) diagnosis, which overcomes the drawbacks inherent with the subjective diagnostic methods. MicroRNA (miRNA) fingerprints have been explored for disease diagnosis. We performed a meta-analysis to examine miRNA diagnostic value for SZ and further validated the meta-analysis results. Using following terms: schizophrenia/SZ, microRNA/miRNA, diagnosis, sensitivity and specificity, we searched databases restricted to English language and reviewed all articles published from January 1990 to October 2016. All extracted data were statistically analyzed and the results were further validated with peripheral blood mononuclear cells (PBMNCs) isolated from patients and healthy controls using RT-qPCR and receiver operating characteristic (ROC) analysis. A total of 6 studies involving 330 patients and 202 healthy controls were included for meta-analysis. The pooled sensitivity, specificity and diagnostic odds ratio were 0.81 (95% CI: 0.75-0.86), 0.81 (95% CI: 0.72-0.88) and 18 (95% CI: 9-34), respectively; the positive and negative likelihood ratio was 4.3 and 0.24 respectively; the area under the curve in summary ROC was 0.87 (95% CI: 0.84-0.90). Validation revealed that miR-181b-5p, miR-21-5p, miR-195-5p, miR-137, miR-346 and miR-34a-5p in PBMNCs had high diagnostic sensitivity and specificity in the context of schizophrenia. In conclusion, blood-derived miRNAs might be promising biomarkers for SZ diagnosis.
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Ben-Shachar D. Mitochondrial multifaceted dysfunction in schizophrenia; complex I as a possible pathological target. Schizophr Res 2017; 187:3-10. [PMID: 27802911 DOI: 10.1016/j.schres.2016.10.022] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/10/2016] [Accepted: 10/14/2016] [Indexed: 01/09/2023]
Abstract
Mitochondria are key players in various essential cellular processes beyond being the main energy supplier of the cell. Accordingly, they are involved in neuronal synaptic transmission, neuronal growth and sprouting and consequently neuronal plasticity and connectivity. In addition, mitochondria participate in the modulation of gene transcription and inflammation as well in physiological responses in health and disease. Schizophrenia is currently regarded as a neurodevelopmental disorder associated with impaired immune system, aberrant neuronal differentiation and abnormalities in various neurotransmitter systems mainly the dopaminergic, glutaminergic and GABAergic. Ample evidence has been accumulated over the last decade indicating a multifaceted dysfunction of mitochondria in schizophrenia. Indeed, mitochondrial deficit can be of relevance for the majority of the pathologies observed in this disease. In the present article, we overview specific deficits of the mitochondria in schizophrenia, with a focus on the first complex (complex I) of the mitochondrial electron transport chain (ETC). We argue that complex I, being a major factor in the regulation of mitochondrial ETC, is a possible key modulator of various functions of the mitochondria. We review biochemical, molecular, cellular and functional evidence for mitochondrial impairments and their possible convergence to impact in-vitro neuronal differentiation efficiency in schizophrenia. Mitochondrial function in schizophrenia may advance our knowledge of the disease pathophysiology and open the road for new treatment targets for the benefit of the patients.
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Affiliation(s)
- Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Technion-IIT, Haifa, Israel.
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The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Transl Psychiatry 2017; 7:e998. [PMID: 28072411 PMCID: PMC5545732 DOI: 10.1038/tp.2016.268] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/22/2016] [Accepted: 11/13/2016] [Indexed: 01/09/2023] Open
Abstract
To date, diagnosis of schizophrenia is still based on clinical interviews and careful observations, which is subjective and variable, and can lead to misdiagnosis and/or delay in diagnosis. As early intervention in schizophrenia is important in improving outcomes, objective tests that can be used for schizophrenia diagnosis or treatment monitoring are thus in great need. MicroRNAs (miRNAs) negatively regulate target gene expression and their biogenesis is tightly controlled by various factors including transcription factors (TFs). Dysregulation of miRNAs in brain tissue and peripheral blood mononuclear cells (PBMNCs) from patients with schizophrenia has been well documented, but analysis of the sensitivity and specificity for potential diagnostic utility of these alternations is limited. In this study, we explored the TF-miRNA-30-target gene axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Using bioinformatics analysis, we retrieved all TFs that control the biogenesis of miRNA 30 members as well as all target genes that are regulated by miRNA-30 members. Further, reverse transcription-quantitative PCR analysis revealed that the early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated, whereas neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs from patients in acute psychotic state. Antipsychotics treatment resulted in the elevation of EGR1 and miR-30a-5p but the reduction of NEUROD1. Receiver operating characteristic analysis showed that the EGR1-miR-30a-5p-NEUROD1 axis possessed significantly greater diagnostic value than miR-30a-5p alone. Our data suggest the EGR1-miR-30a-5p-NEUROD1 axis might serve as a promising biomarker for diagnosis and treatment monitoring for those patients in acute psychotic state.
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Bergman O, Ben-Shachar D. Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia: Possible Interactions with Cellular Processes. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2016; 61:457-69. [PMID: 27412728 PMCID: PMC4959648 DOI: 10.1177/0706743716648290] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mitochondria are key players in the generation and regulation of cellular bioenergetics, producing the majority of adenosine triphosphate molecules by the oxidative phosphorylation system (OXPHOS). Linked to numerous signaling pathways and cellular functions, mitochondria, and OXPHOS in particular, are involved in neuronal development, connectivity, plasticity, and differentiation. Impairments in a variety of mitochondrial functions have been described in different general and psychiatric disorders, including schizophrenia (SCZ), a severe, chronic, debilitating illness that heavily affects the lives of patients and their families. This article reviews findings emphasizing the role of OXPHOS in the pathophysiology of SCZ. Evidence accumulated during the past few decades from imaging, transcriptomic, proteomic, and metabolomic studies points at OXPHOS deficit involvement in SCZ. Abnormalities have been reported in high-energy phosphates generated by the OXPHOS, in the activity of its complexes and gene expression, primarily of complex I (CoI). In addition, cellular signaling such as cAMP/protein kinase A (PKA) and Ca(+2), neuronal development, connectivity, and plasticity have been linked to OXPHOS function and are reported to be impaired in SCZ. Finally, CoI has been shown as a site of interaction for both dopamine (DA) and antipsychotic drugs, further substantiating its role in the pathology of SCZ. Understanding the role of mitochondria and the OXPHOS in particular may encourage new insights into the pathophysiology and etiology of this debilitating disorder.
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Affiliation(s)
- Oded Bergman
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Technion-IIT, Haifa, Israel B. Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel
| | - Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Technion-IIT, Haifa, Israel B. Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel
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Lai CY, Scarr E, Udawela M, Everall I, Chen WJ, Dean B. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World J Psychiatry 2016; 6:102-17. [PMID: 27014601 PMCID: PMC4804259 DOI: 10.5498/wjp.v6.i1.102] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/20/2015] [Accepted: 12/17/2015] [Indexed: 02/05/2023] Open
Abstract
Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophrenia-associated phenotype. We sorted the studies into six categories which include: (1) brain-derived neurotrophic factor; (2) inflammation and immune function; (3) neurochemistry; (4) oxidative stress response and metabolism; (5) epigenetics and microRNA; and (6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, blood oriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.
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Mitochondrial complex I and III mRNA levels in bipolar disorder. J Affect Disord 2015; 184:160-3. [PMID: 26093828 DOI: 10.1016/j.jad.2015.05.060] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 05/11/2015] [Accepted: 05/31/2015] [Indexed: 11/22/2022]
Abstract
BACKGROUND Studies that have focused on the mitochondrial electron transport chain indicate that bipolar disorder (BD) is associated with pathology in mitochondrial function. These pathological processes occur in the brain circuits that regulate affective functions, emotions, and motor behaviors. The present study aimed to determine the relationship between mitochondrial complex dysfunction and BD. METHODS The BD group included 32 male patients diagnosed with first-episode manic BD. The control group included 35 sociodemographically matched healthy males. Messenger ribonucleic acid (mRNA) was isolated from peripheral blood samples obtained from the patients and control group, and the mRNA levels of the NDUFV1, NDUFV2, and NDUFS1 genes of mitochondrial complex I and the UQCR10 gene of mitochondrial complex III were investigated. RESULTS Significant differences were identified in complex I gene mRNA levels between the BD group (n = 32) and the control group (n = 35) for the following genes: NDUFV1 (P = 0.01), NDUFV2 (P < 0.01), and NDUFS1 (P = 0.02). The UQCR10 gene (complex III) mRNA level did not differ between the groups (P = 0.1). The mRNA levels of the four genes studied were lower at the 3-month follow-up; however, these differences were not significant (P > 0.05). LIMITATIONS All of the BD patients were in manic episodes; thus, we were unable to separately compare these levels with those during depressive and euthymic episodes. CONCLUSIONS The mRNA levels of all of the genes representing the subunits of mitochondrial complex I (NDUFV1, NDUFV2, and NDUFS1) were significantly higher in the present study's BD patients during manic episodes than in the controls. With the data obtained from further research, biomarkers that could be used for the diagnosis and follow-up of neuropsychiatric disorders may be discovered.
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Vousooghi N, Zarei SZ, Sadat-Shirazi MS, Eghbali F, Zarrindast MR. mRNA expression of dopamine receptors in peripheral blood lymphocytes of computer game addicts. J Neural Transm (Vienna) 2015; 122:1391-8. [DOI: 10.1007/s00702-015-1408-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/04/2015] [Indexed: 12/24/2022]
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Toker L, Agam G. Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects. Neuropsychiatr Dis Treat 2015; 11:2441-7. [PMID: 26442764 PMCID: PMC4590577 DOI: 10.2147/ndt.s70346] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson's, Alzheimer's, Huntington's, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, "mitochondrial dysfunction" became more of a cliché than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions.
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Affiliation(s)
- Lilach Toker
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
| | - Galila Agam
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel ; Mental Health Center, Beer-Sheva, Israel
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Akarsu S, Torun D, Bolu A, Erdem M, Kozan S, Ak M, Akar H, Uzun Ö. Mitochondrial complex I and III gene mRNA levels in schizophrenia, and their relationship with clinical features. J Mol Psychiatry 2014; 2:6. [PMID: 25713723 PMCID: PMC4307627 DOI: 10.1186/s40303-014-0006-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 11/24/2014] [Indexed: 11/17/2022] Open
Abstract
Background The etiology of schizophrenia is not precisely known; however, mitochondrial function and cerebral energy metabolism abnormalities were determined to be possible factors associated with the etiology of schizophrenia. Impaired mitochondrial function negatively affects neuronal plasticity, and can cause cognitive deficits and behavioral abnormalities observed during the clinical course of schizophrenia. The present study aimed to investigate the relationship between the clinical features of schizophrenia, and mitochondrial complex activation, based on measurement of mRNA levels in the NDUFV1, NDUFV2, NDUFS1, and UQCR10 genes involved in the peripheral mitochondrial complex. Methods The study included 138 schizophrenia patients and 42 healthy controls. The schizophrenia group was divided into a chronic schizophrenia subgroup (n = 84) and a first-episode schizophrenia subgroup (n = 54). The symptoms profile and severity of disorder were evaluated using the Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), and Brief Psychiatric Rating Scale (BPRS). Results The level of mRNA expression of NDUFV1, NDUFV2, and NDUFS1 was significantly higher in the schizophrenia group than in the control group. The mRNA level of NDUFV2 was positively correlated with BPRS and SAPS scores in the first-episode schizophrenia subgroup. Conclusion The findings showed that there was a positive correlation between gene mRNA levels and psychotic symptomatology, especially positive symptoms. Our results suggest that mRNA levels of the NDUFV1, NUDFV2, and NDUFS1 genes of complex I of the mitochondrial electron transport chain might become a possible peripheral marker for the diagnosis of schizophrenia.
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Affiliation(s)
- Süleyman Akarsu
- Department of Psychiatry, Aksaz Military Hospital, Marmaris, Muğla Turkey
| | - Deniz Torun
- Department of Medical Genetics, Gülhane Military Medical Faculty, Ankara, Turkey
| | - Abdullah Bolu
- Aircrew's Health Research and Training Center, Eskişehir, Turkey
| | - Murat Erdem
- Department of Psychiatry, Gülhane Military Medical Faculty, Ankara, Turkey
| | - Salih Kozan
- Department of Medical Genetics, Gülhane Military Medical Faculty, Ankara, Turkey
| | - Mehmet Ak
- Department of Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Hatice Akar
- Department of Medical Genetics, Gülhane Military Medical Faculty, Ankara, Turkey
| | - Özcan Uzun
- Department of Psychiatry, Gülhane Military Medical Faculty, Ankara, Turkey
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Grünblatt E, Geißler J, Jacob CP, Renner T, Müller M, Bartl J, Gross-Lesch S, Riederer P, Lesch KP, Walitza S, Gerlach M, Schmitt A. Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood. ACTA ACUST UNITED AC 2012; 4:77-84. [DOI: 10.1007/s12402-012-0074-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Accepted: 04/24/2012] [Indexed: 12/18/2022]
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Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschläger L, Walitza S, Renner T, Gerlach M, Thome J, Romanos M. Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatry 2011; 12 Suppl 1:104-8. [PMID: 21906006 DOI: 10.3109/15622975.2011.600297] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES In absence of objective clinical characteristics the identification of peripheral biomarkers in neuropsychiatric disorders is highly relevant for the diagnostic process and an individualized therapy. We analyzed mRNA-expression of monoaminergic candidate genes (DRD4, DRD5, TPH1) in peripheral tissue of patients with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), highly comorbid with ADHD, searching for possible molecular markers for these disorders. METHODS mRNA was obtained from children and adolescents with ADHD (n = 51) and ASD (n = 26), diagnosed according to ICD-10 criteria, as well as healthy controls (n = 39). mRNA expression was determined via quantitative realtime PCR (qRT-PCR) from whole blood cells. RESULTS The concentrations of DRD4-mRNA in the whole blood were significantly lower in ADHD and ASD children (19 of 26 comorbid with ADHD) compared to healthy controls. ASD patients revealed a significantly decreased DRD5 mRNA expression in comparison to the two other groups. CONCLUSIONS Alterations in mRNA expression patterns provide further evidence for a relevant effect of the respective candidate genes in the pathophysiology of ADHD. Given their potential as biomarkers mRNA expression patterns may be useful tools in (differential-) diagnostic procedures of ADHD and ASD. Future studies may determine the sensitivity and specificity of these putative biomarkers in larger samples including further neuropsychiatric diagnoses.
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Affiliation(s)
- Regina Taurines
- Hospital of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
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Taurines R, Thome J, Duvigneau JC, Forbes-Robertson S, Yang L, Klampfl K, Romanos J, Müller S, Gerlach M, Mehler-Wex C. Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia. Eur Child Adolesc Psychiatry 2010; 19:441-8. [PMID: 19894076 DOI: 10.1007/s00787-009-0074-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Accepted: 10/16/2009] [Indexed: 12/26/2022]
Abstract
Searching for a peripheral biological marker for schizophrenia, we previously reported on elevated mitochondrial complex I 75-kDa subunit mRNA-blood concentrations in early onset schizophrenia (EOS). The aim of this study was to further evaluate the utility of this gene as a potential marker for schizophrenia. Both-schizophrenia and autism-are suggested to be neuronal maldevelopmental disorders with reports of mitochondrial dysfunction and increased oxidative stress. Therefore we have investigated the expression levels of mitochondrial complex I 75-kDa subunit mRNA in whole blood of children with autistic spectrum disorder (ASD) and a group of adolescent acute first-episode EOS patients in comparison to matched controls. We have found that compared to the respective controls only the group of EOS patients-and not the ASD group-showed a significantly altered expression of the complex I 75-kDa subunit mRNA. Although further studies are necessary to test for the specificity of this marker, our findings point to the potential use of the mitochondrial complex I as a biomarker for schizophrenia.
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Affiliation(s)
- Regina Taurines
- Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany.
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Ben-Shachar D. The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia. J Neural Transm (Vienna) 2010; 116:1383-96. [PMID: 19784753 DOI: 10.1007/s00702-009-0319-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Accepted: 09/14/2009] [Indexed: 12/15/2022]
Abstract
Schizophrenia is currently believed to result from variations in multiple genes, each contributing a subtle effect, which combines with each other and with environmental stimuli to impact both early and late brain development. At present, schizophrenia clinical heterogeneity as well as the difficulties in relating cognitive, emotional and behavioral functions to brain substrates hinders the identification of a disease-specific anatomical, physiological, molecular or genetic abnormality. Mitochondria play a pivotal role in many essential processes, such as energy production, intracellular calcium buffering, transmission of neurotransmitters, apoptosis and ROS production, all either leading to cell death or playing a role in synaptic plasticity. These processes have been well established as underlying altered neuronal activity and thereby abnormal neuronal circuitry and plasticity, ultimately affecting behavioral outcomes. The present article reviews evidence supporting a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, impairments in the oxidative phosphorylation system (OXPHOS) as well as altered mitochondrial-related gene expression. Abnormalities in mitochondrial complex I, which plays a major role in controlling OXPHOS activity, are discussed. Among them are schizophrenia specific as well as disease-state-specific alterations in complex I activity in the peripheral tissue, which can be modulated by DA. In addition, CNS and peripheral abnormalities in the expression of three of complex I subunits, associated with parallel alterations in their transcription factor, specificity protein 1 (Sp1) are reviewed. Finally, this review discusses the question of disease specificity of mitochondrial pathologies and suggests that mitochondria dysfunction could cause or arise from anomalities in processes involved in brain connectivity.
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Affiliation(s)
- Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center and Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Technion IIT, Haifa, Israel.
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18
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Stober G, Ben-Shachar D, Cardon M, Falkai P, Fonteh AN, Gawlik M, Glenthoj BY, Grunblatt E, Jablensky A, Kim YK, Kornhuber J, McNeil TF, Muller N, Oranje B, Saito T, Saoud M, Schmitt A, Schwartz M, Thome J, Uzbekov M, Durany N, Riederer P. Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers. World J Biol Psychiatry 2009; 10:127-55. [PMID: 19396704 DOI: 10.1080/15622970902898980] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Objective. The phenotypic complexity, together with the multifarious nature of the so-called "schizophrenic psychoses", limits our ability to form a simple and logical biologically based hypothesis for the disease group. Biological markers are defined as biochemical, physiological or anatomical traits that are specific to particular conditions. An important aim of biomarker discovery is the detection of disease correlates that can be used as diagnostic tools. Method. A selective review of the WFSBP Task Force on Biological Markers in schizophrenia is provided from the central nervous system to phenotypes, functional brain systems, chromosomal loci with potential genetic markers to the peripheral systems. Results. A number of biological measures have been proposed to be correlated with schizophrenia. At present, not a single biological trait in schizophrenia is available which achieves sufficient specificity, selectivity and is based on causal pathology and predictive validity to be recommended as diagnostic marker. Conclusions. With the emergence of new technologies and rigorous phenotypic subclassification the identification of genetic bases and assessment of dynamic disease related alterations will hopefully come to a new stage in the complex field of psychiatric research.
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Affiliation(s)
- Gerald Stober
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wurzburg, Wurzburg, Germany.
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Martins-de-Souza D, Gattaz WF, Schmitt A, Novello JC, Marangoni S, Turck CW, Dias-Neto E. Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation. BMC Psychiatry 2009; 9:17. [PMID: 19405953 PMCID: PMC2684104 DOI: 10.1186/1471-244x-9-17] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2008] [Accepted: 04/30/2009] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Schizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing. METHODS We performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area - BA22p) identifying by mass spectrometry several protein expression alterations that could be related to the disease. RESULTS Our analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuron-specific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6) and glial fibrillary acidic protein (GFAP) were confirmed by western blot in schizophrenia prefrontal cortex. CONCLUSION Our data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease.
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Affiliation(s)
- Daniel Martins-de-Souza
- Laboratório de Neurociências, Instituto de Psiquiatria, Faculdade de Medicina da USP, Rua Dr, Ovídio Pires de Campos, no 785, São Paulo, SP, CEP 05403-010, Brazil.
| | - Wagner F Gattaz
- Laboratório de Neurociências, Instituto de Psiquiatria, Faculdade de Medicina da USP, Rua Dr. Ovídio Pires de Campos, no 785, São Paulo, SP, CEP 05403-010, Brazil
| | - Andrea Schmitt
- Department of Psychiatry, Von Siebold Str. 5, University of Goettingen, 37075 Goettingen, Germany
| | - José C Novello
- Max Planck Institute of Psychiatry, Kraepelinstrasse 2, D-80804, Munich, Germany
| | - Sérgio Marangoni
- Max Planck Institute of Psychiatry, Kraepelinstrasse 2, D-80804, Munich, Germany
| | - Christoph W Turck
- Departamento de Bioquímica, Instituto de Biologia, UNICAMP, CEP 13083-970, Campinas, SP, Brazil
| | - Emmanuel Dias-Neto
- Laboratório de Neurociências, Instituto de Psiquiatria, Faculdade de Medicina da USP, Rua Dr. Ovídio Pires de Campos, no 785, São Paulo, SP, CEP 05403-010, Brazil,University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, 77030, Houston, Texas, USA
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Brenner-Lavie H, Klein E, Ben-Shachar D. Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells. Biochem Pharmacol 2009; 78:85-95. [PMID: 19447227 DOI: 10.1016/j.bcp.2009.03.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2009] [Revised: 03/23/2009] [Accepted: 03/24/2009] [Indexed: 12/17/2022]
Abstract
Accumulating evidence suggests a role for mitochondria in synaptic potentiation and neurotransmission as well as in morphogenesis and plasticity of spines and synapses. However, studies investigating the ability of neurotransmitters to reciprocally affect mitochondrial function are sparse. In the present study we investigated whether dopamine can affect mitochondrial function in intact neuronal cells. We have shown that short- or long-term exposure of human neuroblastoma SH-SY5Y cells to dopamine (DA) inhibited mitochondrial respiration. This inhibition was associated with an increase in DA intracellular levels, and was prevented by the DA membrane transporter inhibitors, cocaine and GBR-12909. DA inhibited respiration driven through complex I but not through complexes II or III, in line with DA ability to specifically inhibit complex I activity in mitochondrial preparations. The effect of DA on complex I was not associated with altered expression of three subunits of complex I, which were formerly reported abnormal in DA-related pathologies. DA effects on respiration were not due to its ability to form reactive oxygen species. Antipsychotic drugs, which compete with DA on its receptors and inhibit complex I activity, also decreased complex I driven mitochondrial respiration. These findings may suggest that DA, which is taken up by neurons, can affect mitochondria and thereby neurotransmission and synaptic plasticity. Such a mechanism may be of relevance to DA-related non-degenerative pathologies such as schizophrenia.
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Affiliation(s)
- Hanit Brenner-Lavie
- Research Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel
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Expression of neuronal calcium sensor-1 (NCS-1) is decreased in leukocytes of schizophrenia and bipolar disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:229-34. [PMID: 19091302 DOI: 10.1016/j.pnpbp.2008.11.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 11/10/2008] [Accepted: 11/11/2008] [Indexed: 02/07/2023]
Abstract
Schizophrenia (SCZ) and bipolar disorder (BPD) are severe illnesses representing an enormous social, familiar and individual burden that affect 1% of the population world-wide. Several evidences indicate abnormalities of the dopamine system in both SCZ and BPD. Neuronal calcium sensor-1 (NCS-1) is a protein that has many functions in neurotransmission such as inhibition of dopamine D(2) receptor desensitization, regulation of ionic channels and enhancement of exocytosis of neurotransmitters. In addition, NCS-1 protein expression and mRNA levels were found increased in pre-frontal cortex (PFC) of SCZ and BPD patients. NCS-1 expression in neural and neuroendocrine cells is well documented and, recently, it was shown that NCS-1 is also expressed in mast cells and neutrophils. NCS-1 has important functions in mast cells since it stimulates Fc epsilon RI-triggered exocytosis and the release of arachidonic acid metabolites. Then, due to the known close relation between the nervous and immune systems, we sought to investigate the NCS-1 expression in lymphocytes and monocytes (CD4+ T lymphocytes, CD56+ NK cells, CD19+ B lymphocytes and CD14+ monocytes) of SCZ and BPD patients. Using flow cytometry, our results have shown that NCS-1 expression was diminished in CD4+T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of BPD patients and also decreased in CD4+ T lymphocytes and CD56+ NK cells of SCZ patients. Results suggest that immune cells might be a cellular model for studies with SCZ and BPD patients considering NCS-1 functions. Efforts need to be done to investigate the motive of the decreased percentage of immune cells expressing NCS-1 in patients with SCZ and BPD.
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Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis. J Neural Transm (Vienna) 2008; 116:275-89. [DOI: 10.1007/s00702-008-0156-y] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2008] [Accepted: 10/29/2008] [Indexed: 12/15/2022]
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Ben-Shachar D, Karry R. Neuroanatomical pattern of mitochondrial complex I pathology varies between schizophrenia, bipolar disorder and major depression. PLoS One 2008; 3:e3676. [PMID: 18989376 PMCID: PMC2579333 DOI: 10.1371/journal.pone.0003676] [Citation(s) in RCA: 156] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2008] [Accepted: 10/20/2008] [Indexed: 11/19/2022] Open
Abstract
Background Mitochondrial dysfunction was reported in schizophrenia, bipolar disorderand major depression. The present study investigated whether mitochondrial complex I abnormalities show disease-specific characteristics. Methodology/Principal Findings mRNA and protein levels of complex I subunits NDUFV1, NDUFV2 and NADUFS1, were assessed in striatal and lateral cerebellar hemisphere postmortem specimens and analyzed together with our previous data from prefrontal and parieto-occipital cortices specimens of patients with schizophrenia, bipolar disorder, major depression and healthy subjects. A disease-specific anatomical pattern in complex I subunits alterations was found. Schizophrenia-specific reductions were observed in the prefrontal cortex and in the striatum. The depressed group showed consistent reductions in all three subunits in the cerebellum. The bipolar group, however, showed increased expression in the parieto-occipital cortex, similar to those observed in schizophrenia, and reductions in the cerebellum, yet less consistent than the depressed group. Conclusions/Significance These results suggest that the neuroanatomical pattern of complex I pathology parallels the diversity and similarities in clinical symptoms of these mental disorders.
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Affiliation(s)
- Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry Rambam Medical Center and B. Rappaport Faculty of Medicine Technion, Haifa, Israel.
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Ben-Shachar D, Nadri C, Karry R, Agam G. Mitochondrial complex I subunits are altered in rats with neonatal ventral hippocampal damage but not in rats exposed to oxygen restriction at neonatal age. J Mol Neurosci 2008; 38:143-51. [PMID: 18779937 DOI: 10.1007/s12031-008-9144-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2008] [Accepted: 08/11/2008] [Indexed: 11/26/2022]
Abstract
Several independent lines of evidence suggest mitochondrial dysfunction in schizophrenia in brain and periphery, including mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system, and altered mitochondrial-related gene expression. In an attempt to decipher whether mitochondrial complex I abnormality in schizophrenia is a core pathophysiological process or is attributable to medication, we studied two animal models of schizophrenia related to the neurodevelopmental hypothesis of this disorder. Protein levels of complex I subunits, 24, 51, and 75 kDa, were assessed in neonatal ventral hippocampal lesion rat model and in rats exposed to hypoxia at a neonatal age. In the prefrontal cortex, a major anatomical substrate of schizophrenia, neonatal ventral hippocampal lesion induced a significant prepubertal increase and postpubertal decrease in all three subunits of complex I as compared to sham-treated rats, while no change was observed in the cingulate cortex. Neonatal exposure to hypoxia did not affect protein levels of any of the three subunits in the prefrontal cortex. An age-dependent increase in the expression of complex I subunits was observed, which was distorted in the prefrontal cortex by the neonatal ventral hippocampal lesion. Complex I alterations in schizophrenia-related neurodevelopmental rat models appear to be brain region and animal model dependent. The results of this study support previous findings suggesting abnormal complex I expression as a pathological characteristic of schizophrenia rather than an effect of medication.
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Affiliation(s)
- Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine, Technion ITT, P.O. Box 9649, Haifa, 31096, Israel.
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Kakiuchi C, Ishiwata M, Nanko S, Ozaki N, Iwata N, Umekage T, Tochigi M, Kohda K, Sasaki T, Imamura A, Okazaki Y, Kato T. Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:557-64. [PMID: 18081029 DOI: 10.1002/ajmg.b.30643] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude inter-individual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be up-regulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness.
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Affiliation(s)
- Chihiro Kakiuchi
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
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Mehler-Wex C, J. Renner T. Genetische Befunde zu Schizophrenie. ZEITSCHRIFT FUR KINDER-UND JUGENDPSYCHIATRIE UND PSYCHOTHERAPIE 2008; 36:17-26. [DOI: 10.1024/1422-4917.36.1.17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Zusammenfassung: Schizophrene Erkrankungen zeichnen sich durch eine sehr heterogene Symptomatik mit übergreifenden Funktionsstörungen verschiedenster kognitiver Bereiche aus. Die vielfältigen Phänotypen werden durch das Zusammenwirken von genetischer Prädisposition und Umwelteinflüssen erklärt. Pathophysiologische Modelle beinhalten die Dopamin-Überschuss- sowie Glutamat-Mangel-Hypothese, die Radikal-Hypothese und die Hypothese entwicklungsbedingter versus degenerativer Genese. Neben den neurobiologischen Erklärungsansätzen geben Kopplungsstudien mit nachfolgenden Feinkartierungen Hinweise auf potentiell an der Pathophysiologie beteiligte Gene. Den wichtigsten Kandidatengenen, wie Dysbindin (DTNBP1), Neuregulin1 (NRG1) oder DISC-1 (disrupted-in schizophrenia-1), werden Einfluss auf die Signalübertragung sowie der Ausbildung und dem Erhalt der Struktur von neuronalen Netzwerken zugeschrieben. Zu ihnen werden zahlreiche weitere Gene gezählt. Insgesamt ist bei der Pathogenese der Schizophrenie von einer multifaktoriellen Entstehung mit der Interaktion von verschiedenen genetischen und neurobiologischen sowie exogenen Komponenten auszugehen.
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Affiliation(s)
- Claudia Mehler-Wex
- Klinik für Kinder- und Jugendpsychiatrie / Psychotherapie, Universität Ulm
| | - Tobias J. Renner
- Klinik für Kinder- und Jugendpsychiatrie / Psychotherapie, Universität Würzburg
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27
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Ben-Shachar D, Bonne O, Chisin R, Klein E, Lester H, Aharon-Peretz J, Yona I, Freedman N. Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:807-13. [PMID: 17329000 DOI: 10.1016/j.pnpbp.2006.12.025] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2006] [Revised: 12/14/2006] [Accepted: 12/28/2006] [Indexed: 01/12/2023]
Abstract
Altered cerebral energy metabolism and mitochondrial dysfunction in periphery and in brain are implicated in the pathophysiology of schizophrenia. This study investigated whether cerebral glucose metabolism (rCGM) abnormalities are linked to altered mitochondrial complex I activity in the periphery, in schizophrenia. Sixteen schizophrenic patients, 8 with total positive PANSS score >or=20 (high positive schizophrenics; HPS), and 8 with total positive score <or=12 (low positive schizophrenics; LPS), and 8 healthy subjects, were analyzed for their complex I activity in platelets mitochondria and underwent FDG-PET scans at rest. Complex I activity was significantly increased only in HPS and was positively correlated with positive PANSS scores. Images were spatially normalized to an SPM template, their intensities normalized based on average brain activity. Hypermetabolism was observed in the basal ganglia, thalamus, amygdala, and brainstem of both patient groups compared with controls, and in LPS patients extended to parts of cerebellum, left and right cingulate gyrus, parietal and frontal lobes. rCGM in basal ganglia and thalamus significantly and positively correlated with complex I activity in the HPS. In the LPS, a negative correlation was identified in the cerebellum and brainstem. In the control group, however, no areas demonstrated significant positive or negative correlation. These results suggest that the correlation between peripheral complex I activity and rCGM in regions implicated in schizophrenia, could be a pathological factor that is differentially expressed in subgroups of schizophrenic patients.
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Affiliation(s)
- Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine Technion IIT, Haifa, Israel.
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Numata S, Ueno SI, Iga JI, Yamauchi K, Hongwei S, Hashimoto R, Takeda M, Kunugi H, Itakura M, Ohmori T. Gene expression in the peripheral leukocytes and association analysis of PDLIM5 gene in schizophrenia. Neurosci Lett 2007; 415:28-33. [PMID: 17287082 DOI: 10.1016/j.neulet.2007.01.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Revised: 12/27/2006] [Accepted: 01/02/2007] [Indexed: 01/08/2023]
Abstract
PDLIM5 modulates neuronal calcium signaling, co-localizes with synaptic vesicles of neurotransmitters and positive association between its gene and schizophrenia was reported but its relation is still ambiguous. The differential expression of the PDLIM5 gene both in the brain and in the lymphoblasts has been found in schizophrenia compared to control subjects. In this study, we measured the expression level of the PDLIM5 gene transcripts in the peripheral leukocytes from 19 medication-free and 21 chronically medicated schizophrenic patients as well as age- and sex-matched control subjects using a quantitative real-time PCR method. The mRNA levels of the PDLIM5 gene in the leukocytes of medication-free schizophrenic patients were significantly higher than those of control subjects. On the other hand, our group has previously shown that its mRNA expression in the leukocytes of medication-free major depressive patients was significantly lower compared with controls. There was no difference in the PDLIM5 mRNA levels between chronic schizophrenic patients with antipsychotic medication and their controls. Further, we failed to find any genetic association between the PDLIM5 gene and schizophrenia with six single nucleotide polymorphics (SNPs) of the PDLIM5 gene in Japanese subjects (279 subjects each) and there was no significant relation between PDLIM5 gene and schizophrenia with the haplotype analysis (P=0.48), either. We suggest that the higher expression levels of the PDLIM5 mRNA in the peripheral leukocytes may be a candidate marker for medication-free schizophrenic patients.
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Affiliation(s)
- Shusuke Numata
- Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-8-15 Kuramoto-cho, Tokushima 770-8503, Japan
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Archer T, Beninger RJ. Movement disorders: neurodevelopment and neurobehavioural expression. J Neural Transm (Vienna) 2006; 114:XXXIII-XLI. [PMID: 17024325 DOI: 10.1007/s00702-006-0572-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2006] [Accepted: 07/31/2006] [Indexed: 12/15/2022]
Abstract
Braak and co-workers have recently shown that movement disorders such as Parkinson's disease develop progressively over years with early neuronal losses in brainstem regions caudal to the substantia nigra. The relevance of this finding to notions of comorbidity between movement disorders and psychiatric symptoms was recognised at the recent meeting concerning, "Implications of Comorbidity for the Etiology and Treatment of Neuropsychiatric Disorders" held in Oct. 2005 in Mazagon, Spain. The identification of stages in the early development of neurodegenerative disorders appeared to unify multiple, diverse findings. These included: novel therapeutic innovations for Parkinson's disease, Alzheimer's disease and depression in the aged; the neurochemical ontogeny of drug-induced oral dyskinesias; the types of chemical agents abused in neuropsychiatric states; postnatal iron overload effects upon the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expression of movement disorders; and the spectrum of motor symptoms expressed in schizophrenia and attention deficit hyperactivity disorder and the eventual treatment of these disorders. A continued focus on a number of neuropsychiatric diseases as progressive disorders may lead to further advances in understanding their etiology and in developing better therapeutics.
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Affiliation(s)
- T Archer
- Department of Psychology, University of Göteborg, Göteborg, Sweden.
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