Abstract
Modulator of apoptosis 1 (MOAP-1) is a Bcl-2-associated X Protein (BAX)-associating protein that plays an important role in regulating apoptosis. It is highly enriched in the brain but its function in this organ remains unknown. Studies on BAX−/− mice suggested that disruption of programmed cell death may lead to abnormal emotional states. We thus hypothesize that MOAP-1−/− mice may also display stress-related behavioral differences and perhaps involved in stress responses in the brain and investigated if a depression-like trait exists in MOAP-1−/− mice, and if so, whether it is age related, and how it relates to central serotonergic stress response in the dorsal raphe nucleus. Young MOAP-1−/− mice exhibit depression-like behavior, in the form of increased immobility time when compared to age-matched wild-type mice in the forced swimming test, which is abolished by acute treatment of fluoxetine. This is supported by data from the tail suspension and sucrose preference tests. Repeated forced swimming stress causes an up-regulation of tryptophan hydroxylase 2 (TPH2) and a down-regulation of brain-derived neurotrophic factor (BDNF) in the dorsal raphe nucleus (DRN) in young wild-type (WT) control mice. In contrast, TPH2 up-regulation was not observed in aged WT mice. Interestingly, such a stress response appears absent in both young and aged MOAP-1−/− mice. Aged MOAP-1−/− and WT mice also have similar immobility times on the forced swimming test. These data suggest that MOAP-1 is required in the regulation of stress response in the DRN. Crosstalk between BDNF and 5-HT appears to play an important role in this stress response.
Highlights
Modulator of apoptosis 1 (MOAP-1), a Bcl-2-associated X Protein (BAX)-associating BH-3 like protein, is a short-lived protein enriched in the outer membrane of mitochondria [1, 2]
No significant differences were observed between MOAP-1−/− and WT controls in the rotarod test (Fig. 1d), elevated plus maze (EPM) (Fig. 1e), open field test (OFT) (Fig. 1f), and light dark box (LDB) (Fig. 1g)
As BAX−/− mice are known to exhibit increased immobilization time in forced swimming test (FST) [4], we checked the expression of BAX in MOAP-1−/− mice and found normal BAX expression when compared to WT mice (Supplementary Fig. S1A)
Summary
Modulator of apoptosis 1 (MOAP-1), a BAX-associating BH-3 like protein, is a short-lived protein enriched in the outer membrane of mitochondria [1, 2]. The internalized TNF-R1 complexes with MOAP-1 and Ras association domain family 1A (RASSF1A), and triggers a conformational change in MOAP-1 to expose its BH3-like domain for BAX association. BAX becomes activated and translocates to the mitochondrial outer membrane to initiate apoptosis by releasing cytochrome c and apoptogenic factors. It has been noted that these mice develop normally to adulthood and are fertile [5]. In our hands, they do not appear to differ significantly from MOAP-1+/+ mice in appearance, body weight (Fig. 5a), and fertility (litter size 6.3 ± 1.1 vs 6.1 ± 0.6 of WT (n = 4), 4 litters in 6 months for both). While we had not checked the natural lifespan of these MOAP-1−/− mice, the mean ages of our aged mice used in this study were 23.5 ± 0.4 and 23.9 ± 0.4 months (range 22–26 months) for MOAP1−/− and MOAP-1+/+ mice, respectively, which is approximately 90% of the reported average lifespan of C57/BL6 mice [6, 7]
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