Summary: Researchers report genetic alterations that modulate stress have been identified in children who are at risk of developing bipolar disorder.
Source: UT Health Science Center Houston.
Genetic alterations that can be modulated by stress have been identified in children at high risk for bipolar disorder, according to a recently published study by researchers at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth). Results appeared in Translational Psychiatry.
“We’ve known that children of patients with bipolar disorder have a higher risk of developing the illness but the biological mechanisms are largely unknown,” said Gabriel R. Fries, Ph.D., first author and a post-doctoral research fellow in the Department of Psychiatry and Behavioral Sciences at McGovern Medical School at UTHealth. “By analyzing the blood of children of controls and comparing it to children of bipolar patients, we identified several genes or markers that can explain the increased risk.”
Researchers analyzed peripheral blood mononuclear cells from a total of 18 children and adolescents in three matched groups: bipolar patients, unaffected offspring of bipolar parents and children of parents with no history of psychiatric disorders.
The analysis revealed that, compared to children in the control group, bipolar patients and unaffected offspring of bipolar parents had genetic alterations that can influence the response to stress.
“All combine to modulate the response to stress in these children,” Fries said. “We know from clinical studies of behavior and the environment that when children are chronically exposed to stressors, they are at a higher risk of developing bipolar disorder. Bipolar parents may struggle because of their disease, leading to higher environmental stress. Their children, because of the genetic markers they have, could be more vulnerable to stress.”
The genetic alterations that researchers discovered were validated in blood samples of unrelated adult bipolar patients, Fries said.
New avenues of research could include the effects of reducing environmental stress, as well as whether pharmacological agents might be able to reverse the genetic alternations in vulnerable children before the disorder develops.
Blood samples for the research came from the innovative Pediatric Bipolar Registry at the UTHealth Center of Excellence on Mood Disorders.
Senior author is Jair C. Soares, M.D., Ph.D., professor, chairman and the Pat R. Rutherford, Jr. Endowed Chair in the Department of Psychiatry and Behavioral Sciences at McGovern Medical School.
Co-authors from McGovern Medical School are Iram Kazimi, M.D., assistant professor; Cristian P. Zeni, M.D., Ph.D., assistant professor and director of the Mood Disorders Clinic for Children and Adolescents; Giovana Zunta-Soares, M.D., assistant professor and director of the Mood Disorders Clinical Trial Program; Consuelo Walss-Bass, Ph.D., associate professor and co-director of the Translational Psychiatry Program; and Joao L. de Quevedo, M.D., Ph.D., professor, vice-chair and director of the Translational Psychiatry Program. Soares, Walss-Bass and de Quevedo are faculty members of the Neuroscience Graduate Program at The University of Texas MD Anderson Center Center UTHealth Graduate School of Biomedical Sciences.
Funding: The research was supported in part by grants from the Pat Rutherford, Jr. Endowed Chair in Psychiatry and the John S. Dunn Foundation.
Source: Deborah Mann Lake – UT Health Science Center Houston
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients” by G Scaini, G R Fries, S S Valvassori, C P Zeni, G Zunta-Soares, M Berk, J C Soares & J Quevedo in Translational Psychiatry. Published online May 2 2017 doi:10.1038/tp.2017.83
Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients
Bipolar disorder (BD) is a severe psychiatric disorder characterized by phasic changes of mood and can be associated with progressive structural brain change and cognitive decline. The numbers and sizes of glia and neurons are reduced in several brain areas, suggesting the involvement of apoptosis in the pathophysiology of BD. Because the changes in mitochondrial dynamics are closely related with the early process of apoptosis and the specific processes of apoptosis and mitochondrial dynamics in BD have not been fully elucidated, we measured the apoptotic pathway and the expression of mitochondrial fission/fusion proteins from BD patients and healthy controls. We recruited 16 patients with BD type I and sixteen well-matched healthy controls and investigated protein levels of several pro-apoptotic and anti-apoptotic factors, as well as the expression of mitochondrial fission/fusion proteins in peripheral blood mononuclear cells (PBMCs).
Our results showed that the levels of the anti-apoptotic proteins Bcl-xL, survivin and Bcl-xL/Bak dimer were significantly decreased, while active caspase-3 protein levels were significantly increased in PBMCs from BD patients. Moreover, we observed the downregulation of the mitochondrial fusion-related proteins Mfn2 and Opa1 and the upregulation of the fission protein Fis1 in PBMCs from BD patients, both in terms of gene expression and protein levels. We also showed a significantly decrease in the citrate synthase activity.
Finally, we found a positive correlation between Mfn2 and Opa1 with mitochondrial content markers, as well as a negative correlation between mitochondrial fission/fusion proteins and apoptotic markers. Overall, data reported here are consistent with the working hypothesis that apoptosis may contribute to cellular dysfunction, brain volume loss and progressive cognitive in BD. Moreover, we show an important relationship between mitochondrial dynamics and the cell death pathway activation in BD patients, supporting the link between mitochondrial dysfunction and the pathophysiology of BD.
“Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients” by G Scaini, G R Fries, S S Valvassori, C P Zeni, G Zunta-Soares, M Berk, J C Soares & J Quevedo in Translational Psychiatry. Published online May 2 2017 doi:10.1038/tp.2017.83