The Reduction of R1, a Novel Repressor Protein for Monoamine Oxidase A, in Major Depressive Disorder

Abstract

The novel transcriptional repressor protein, R1 (JPO2/CDCA7L/RAM2), inhibits monoamine oxidase A (MAO A) gene expression and influences cell proliferation and survival. MAO A is implicated in several neuropsychiatric illnesses and highly elevated in major depressive disorder (MDD); however, whether R1 is involved in these disorders is unknown. This study evaluates the role of R1 in depressed subjects either untreated or treated with antidepressant drugs. R1 protein levels were determined in the postmortem prefrontal cortex of 18 untreated MDD subjects and 12 medicated MDD subjects compared with 18 matched psychiatrically normal control subjects. Western blot analysis showed that R1 was significantly decreased by 37.5% (po0.005) in untreated MDD subjects. The R1 level in medicated MDD subjects was also significantly lower (by 30%; po0.05) compared with control subjects, but was not significantly different compared with untreated MDD subjects. Interestingly, the reduction in R1 was significantly correlated with an increase (approximately 40%; po0.05) in MAO A protein levels within the MDD groups compared with controls. Consistent with the change in MAO A protein expression, the MAO A catalytic activity was significantly greater in both MDD groups compared with controls. These results suggest that reduced R1 may lead to elevated MAO A levels in untreated and treated MDD subjects; moreover, the reduction of R1 has been implicated in apoptotic cell death and apoptosis has also been observed in the brains of MDD subjects. Therefore, modulation of R1 levels may provide a new therapeutic target in the development of more effective strategies to treat MDD.

Elevated Monoamine Oxidase A Binding During Major Depressive Episodes Is Associated with Greater Severity and Reversed Neurovegetative Symptoms

“…Oxidative stress elicited through overexpression of glyoxalase 1 and glutathione reductase 1 genes or through other methods such as xanthine and xanthine oxidase treatment is associated with anxiety behavior in preclinical models (Hovatta et al, 2005;Salim et al, 2010). Genetic vulnerability toward apoptosis is associated with greater risk of MDD in some human subpopulations (Harlan et al, 2006) and both mRNA and protein levels of R1 (a nuclear transcription factor which facilitates resistance against apoptosis) are reduced in the PFC in MDD (Johnson et al, 2011;Thalmeier et al, 2008).…”

“…In humans, during MDE, greater whole-brain serotonin turnover has been reported (Barton et al, 2008) and this is consistent with greater MAO-A level and/or activity as MAO-A is the primary route of serotonin metabolism in brain. Also, reduced mRNA and levels of nuclear transcription factor R1, which inhibits MAO-A transcription, and elevated levels of TIEG2, a nuclear transcription factor that promotes transcription of MAO-A, were found in postmortem PFC in MDE (Grunewald et al, 2012;Johnson et al, 2011;Ou et al, 2006a, b).…”

“…MAO-A level is highly correlated with MAO-A activity in brain (Nelson et al, 1979;Saura et al, 1992) and indices of MAO-A level in the prefrontal (PFC) and anterior cingulate cortex (ACC) were elevated by 25-40% across the three studies that investigated the most common, early onset MDD (Johnson et al, 2011;Meyer et al, 2006;Meyer et al, 2009). Elevated MAO-A level in these regions in MDE is consistent with other specific findings: MDE is a highstress state, and glucocorticoid administration increases transcription rate and catalytic activity of MAO-A in human neuroblastoma and glioblastoma cell lines (Ou et al, 2006a).…”

“…Although all regions sampled to date tend to demonstrate elevated MAO-A V T during MDE, we prioritized these two regions because the accumulated evidence is greatest for elevated MAO-A level in these two regions (Johnson et al, 2011;Meyer et al, 2006Meyer et al, , 2009 and subregions of these structures are activated during sad mood and negative cognition (Liotti et al, 2002;Ressler and Mayberg, 2007).…”

Greater Monoamine Oxidase A Binding in Alcohol Dependence

“…Previous investigations of MAO-A activity in postmortem brain of AD were primarily negative, with no change reported in prefrontal cortex, and a decrease reported in the hypothalamus and caudate (7,8). Unfortunately, these studies were inconclusive because none of them addressed several recently discovered biases that influence MAO-A levels, such as cigarette smoking (9,10), exposure to current or past major depressive episodes (11)(12)(13), and impulsive-aggressive personality traits (14,15). The latter covary with MAO-A levels, likely because of a neurodevelopmental influence of inherited MAO-A levels (16).…”