Evidence of Altered DNA Integrity in the Brain Regions of Suicidal Victims of Bipolar Depression

Article excerpt

Byline: Mohammed. Mustak, Muralidhar. Hegde, Athira. Dinesh, Gabrielle. Britton, Ruben. Berrocal, K. Rao, N. Shamasundar, K.S.J. Rao, T. Sathyanarayana Rao

Deoxyribonucleic acid (DNA) integrity plays a significant role in cell function. There are limited studies with regard to the role of DNA damage in bipolar affective disorder (BP). In the present study, we have assessed DNA integrity, conformation, and stability in the brain region of bipolar depression (BD) patients (n=10) compared to age-matched controls (n=8). Genomic DNA was isolated from 10 postmortem BD patients' brain regions (frontal cortex, Pons, medulla, thalamus, cerebellum, hypothalamus, Parietal, temporal, occipital lobe, and hippocampus) and from the age-matched control subjects. DNA from the frontal cortex, pons, medulla, and thalamus showed significantly higher number of strand breaks in BD (P <0.01) compared to the age-matched controls. However, DNA from the hippocampus region was intact and did not show any strand breaks. The stability studies also indicated that the melting temperature and ethidium bromide binding pattern were altered in the DNA of BD patients' brain regions, except in the hippocampus. The conformation studies showed B-A or secondary B-DNA conformation (instead of the normal B-DNA) in BD patients' brain regions, with the exception of the hippocampus. The levels of redox metals such as Copper (Cu) and Iron (Fe) were significantly elevated in the brain regions of the sufferers of BD, while the Zinc (Zn) level was decreased. In the hippocampus, there was no change in the Fe or Cu levels, whereas, the Zn level was elevated. There was a clear correlation between Cu and Fe levels versus strand breaks in the brain regions of the BD. To date, as far as we are aware, this is a new comprehensive database on stability and conformations of DNA in different brain regions of patients affected with BD. The biological significance of these findings is discussed here.

Introduction

Bipolar depression (BD) is one of the major psychiatric disorders characterized by recurrent depressive and manic episodes. [sup][1] BD affects about 1% of the population and causes severe neuropsychological impairments. The illness is implicated in functional impairment and represents an important risk factor for suicidal behavior. [sup][2] Twin, adoption and family studies, show that genetic factors also contribute to the etiology of this disorder. [sup][1] More recently, remarkable progress has been made in identifying the changes in the brain, related to the pathophysiology of BD. The neurochemical and brain imaging studies have demonstrated volume loss in the brain, in BD. [sup][3],[4] Studies have also shown a reduction in the numerical density of neurons in several brain regions including the anterior cingulate cortex and the hippocampus of subjects with BD. [sup][5],[6] The above-mentioned studies indicate that cell death plays a significant role in BD. Furthermore, the studies suggest that oxidative stress plays a role in the etiology of BD. [sup][7],[8],[9],[10],[11],[12]

The apoptotic cell death of neurons is hypothesized to have a role in neuropsychiatric disorders. [sup][13],[14],[15] There are limited studies indicating the presence of DNA damage in BD. [sup][11],[15],[16],[17],[18],[19] However, DNA fragmentation has also been reported with neurodegenerative disorders. [sup][20],[21],[22],[23] The aim of the current study is to assess the genomic integrity in terms of DNA fragmentation, conformation, and stability in the different brain regions of BD and to ascertain whether altered genome integrity plays a role in thepathophysiology of BD.

Materials and Methods

Materials

Radiolabeled [sup]3 [H]-TTP (Sp.Act.40Ci/nmol) was purchased from Amersham Radiochemicals, UK. Ribonuclease A (RNAse A), Proteinase k, Deoxyribonuclease I (DNAse I), dATP, dTTP, dCTP, dGTP, low melting agarose, DNA polymerase I (from E. …

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