br Concluding remarks Enhanced membrane

Concluding remarks Enhanced membrane binding upon calcium stimulation in d-cycloserine suggests a pre-requisite step that involves a conformational change in LOX. This might facilitate it to tether to the membrane and regulate enzyme activity. The calcium binding loops and the putative active site entrance 1 are on the same side of the molecule. Thus we speculate that Ca binding and conformational distant movements of N-PLAT domain might facilitate substrate capture. An open-state of zf12-LOZ:Ca, as seen in this study, provides an evidence for the above. This might encompass exposure of hydrophobic residues nearby as discussed earlier [9], [58], [61]. Thus it allows us to propose that zf12-LOX might switch from a closed (calcium-free) to open (calcium-bound) state(s) in solution as a mechanism of activation. The findings for zf12-LOX might hold true for mammalian LOXs and extend our understanding of the mechanism utilized for calcium regulation at molecular level.
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Acknowledgments This work was supported by a grant from the Swedish Research Council (10350). We thank Michaela Mårback for technical assistance and the Protein Science Facility (PSF), Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden for technical support. A.F. is funded by the Karin and Sten Mörtstedt initiative on Anaphylaxis. We also thank Prof. Jill Trewhella for valuable discussions regarding SAXS data processing and the staff at Petra III, P12 beamline, Hamburg and Max IV lab, Lund, for assistance in SAXS data collection.
Introduction Although anxiety disorders generally manifest early in life, the ones that evolve in late life represent a significant clinical problem with prevalence rates of 6%–10% in those aged 55 years or older (Schuurmans and van Balkom, 2011). Presently, it is not known whether, if at all, the pathophysiology and progression of anxiety disorders in the elderly group differs from younger age groups. For example, in both aged and young populations, anxiety disorders are associated with major depressive disorders. However, aged persons have additional medical comorbidities and lifetime exposure to various stressors, which could confer an increased biological vulnerability to the development of disorders characterized with clinical anxiety. The aged brain and young brain differ in several biochemical aspects, among which include the oxidation, metabolism, and signaling of bioactive lipids. Emerging work suggests that precise modulation of bioactive lipids in the brain is crucial for proper functioning, and that dysregulation of lipid oxidation could be involved in a number of neurologic and psychiatric diseases. The 12/15-lipoxygenase (12/15-LO) is a lipid-peroxidizing enzyme that is widely expressed in the central nervous system. It produces hydroxyperoxyeicosatetraenoic acid metabolites from arachidonic acid substrate and has been linked to aging-associated illnesses such as Alzheimer's disease (Chu et al., 2012). However, its role in anxiety has not yet been investigated. The goal of this study was to investigate whether overexpression of 12/15-lipoxygenase impacted anxiety-like behavior in mice. Here, we report that an anxiety phenotype developed in mice overexpressing the 12/15-LO (H12/15-LO) at the age of 15 months, which was absent at 12 months.
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Discussion Aging-related changes in lipid metabolism and homeostasis have been relatively unexplored in the context of neurologic and psychiatric illness until recently. The aging brain is vulnerable to oxidative stress because it is a lipid-rich organ, and processes that oxidize brain lipids contribute to deterioration of neuronal functioning. Indeed, we have previously shown that 12/15-LO activity is associated with aging-associated brain oxidative damage and neuronal injury (Chinnici et al., 2005). Beyond direct neuronal damage through oxidation, lipid dysregulation has also been implicated in anxiogenesis following exposure to Gulf War agents and perinatal fatty acid depletion (Abdullah et al., 2012, Palsdottir et al., 2012). Thus, our current findings extend the importance of 12/15-LO as a molecular player in lipid-mediated anxiogenesis in addition to its known role as a brain pro-oxidant.