The Expression of the Suicide-Associated Gene SKA2 Is Decreased in the Prefrontal Cortex of Suicide Victims but Not of Nonsuicidal Patients

Background: Recent study of genome-wide DNA methylation profiling in the postmortem brain of suicidal and nonsuicidal subjects found that gene expression of spindle and kinetochore associated complex subunit 2 (SKA2) is decreased in the postmortem brain of suicide victims compared with nonsuicidal, nonpsychiatric control subjects. Methods: To determine if decreased SKA2 is specific to suicide and independent of diagnosis, we determined gene and protein expression of SKA2 in the prefrontal cortex obtained from suicide victims (n= 52), nonsuicidal psychiatric subjects (n= 27), and normal controls (n= 24). We determined gene expression by quantitative PCR technique and protein expression by Western blot. The postmortem brain samples were obtained from the Maryland Psychiatric Research Center. Results: We found that protein and gene expression of SKA2 was significantly reduced in the prefrontal cortex of suicide victims compared with normal control subjects and nonsuicidal patients. We also found that SKA2 protein and gene expression in depressed suicide victims, schizophrenic suicide victims, and suicide victims with substance abuse and/or conduct disorders was significantly decreased compared with normal control subjects and also with nonsuicidal depressed or schizophrenic subjects. Conclusions: This study shows that decreased gene and protein expression of SKA2 observed in the prefrontal cortex of suicide victims is specific to suicide, which was not observed in the brain of nonsuicidal patients. It also indicates reduced SKA2 expression in suicide is independent of psychiatric diagnosis, since it is observed in all diagnostic groups studied. Therefore, SKA2 may be a potential biomarker for suicide.

[1]  D. Levey,et al.  Psychiatric blood biomarkers: avoiding jumping to premature negative or positive conclusions , 2015, Molecular Psychiatry.

[2]  W. Eaton,et al.  Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors , 2014 .

[3]  G. Turecki The molecular bases of the suicidal brain , 2014, Nature Reviews Neuroscience.

[4]  Yogesh K. Dwivedi,et al.  Region-specific alterations in glucocorticoid receptor expression in the postmortem brain of teenage suicide victims , 2013, Psychoneuroendocrinology.

[5]  N. Schork,et al.  Discovery and validation of blood biomarkers for suicidality , 2013, Molecular Psychiatry.

[6]  G. Pandey Biological basis of suicide and suicidal behavior , 2013, Bipolar disorders.

[7]  P. Courtet,et al.  The suicidal mind and brain: A review of neuropsychological and neuroimaging studies , 2011, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[8]  Andrew H. Miller,et al.  When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. , 2011, The American journal of psychiatry.

[9]  O. Meijer,et al.  Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed , 2010, Psychoneuroendocrinology.

[10]  R. Medema,et al.  RAMA1 is a novel kinetochore protein involved in kinetochore-microtubule attachment , 2009, Journal of Cell Science.

[11]  J. DeLuca,et al.  Connecting with Ska, a key complex at the kinetochore–microtubule interface , 2009, The EMBO journal.

[12]  J. Yates,et al.  The human kinetochore Ska1 complex facilitates microtubule depolymerization-coupled motility. , 2009, Developmental cell.

[13]  Gustavo Turecki,et al.  Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse , 2009, Nature Neuroscience.

[14]  Stafford L. Lightman,et al.  The HPA axis in major depression: classical theories and new developments , 2008, Trends in Neurosciences.

[15]  D. Ray,et al.  Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor , 2008, The Journal of endocrinology.

[16]  A. Nordström,et al.  DST non-suppression predicts suicide after attempted suicide , 2007, Psychiatry Research.

[17]  E. Nigg,et al.  Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2 , 2006, The EMBO journal.

[18]  Jamie D. Feusner,et al.  The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression. , 2004, Journal of affective disorders.

[19]  S. L. Murphy,et al.  Deaths: final data for 2002. , 2004, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[20]  Yogesh K. Dwivedi,et al.  Decreased catalytic activity and expression of protein kinase C isozymes in teenage suicide victims: a postmortem brain study. , 2004, Archives of general psychiatry.

[21]  L. Hankoff Reducing Suicide: A National Imperative , 2003 .

[22]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[23]  W. Coryell,et al.  The dexamethasone suppression test and suicide prediction. , 2001, The American journal of psychiatry.

[24]  Yogesh K. Dwivedi,et al.  Adrenal glucocorticoids modulate [3H]cyclic AMP binding to protein kinase A (PKA), cyclic AMP-dependent PKA activity, and protein levels of selective regulatory and catalytic subunit isoforms of PKA in rat brain. , 2000, The Journal of pharmacology and experimental therapeutics.

[25]  C. Nemeroff,et al.  Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. , 1998, The Psychiatric clinics of North America.

[26]  C. Nemeroff,et al.  The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. , 1996, Molecular psychiatry.

[27]  G. Pugliese,et al.  Severe Streptococcus pyogenes Infections, United Kingdom, 2003–2004 , 2008, Emerging infectious diseases.

[28]  M. First,et al.  The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. , 1992, Archives of general psychiatry.

[29]  G. Brown Psychoneuroendocrinology of depression. , 1989, Psychiatric journal of the University of Ottawa : Revue de psychiatrie de l'Universite d'Ottawa.

[30]  F. Eugene Yates,et al.  The national center for health statistics , 1973, Annals of Biomedical Engineering.

[31]  Arthur Kleinman,et al.  COMMITTEE ON PATHOPHYSIOLOGY AND PREVENTION OF ADOLESCENT AND ADULT SUICIDE , 2002 .

[32]  M. Soules Dexamethasone suppression. , 1982, Obstetrics and gynecology.