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Renalase, a novel soluble FAD-dependent protein, is synthesized in the brain and peripheral nerves

Molecular Psychiatry volume 15, pages 234–236 (2010)Cite this article

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In the central nervous system (CNS), the oxidative deamination of monoamine neurotransmitters is accomplished by two membrane-bound enzymes: monoamine oxidase (of which there are two isoforms, MAO-A and MAO-B) and semicarbazide-sensitive amine oxidase (SSAO). The combined activities of these proteins are crucial for the regulation of neurotransmitter disposition and, consequently, normal brain function. It is therefore not surprising that MAO-A and B gene polymorphisms and altered expression are implicated in a variety of neurological disorders.1, 2, 3, 4, 5 Moreover, the demonstration that MAO inhibitors, such as iproniazid, were effective antidepressant agents was pivotal in Schildkraut's6 formulation of the catecholamine hypothesis of affective disorders. Here, we report for the first time the identification of a novel flavin adenine dinucleotide (FAD)-dependent protein, renalase, in various regions of the CNS. We show that the renalase gene is expressed in the hypothalamus and peripheral nerves. Furthermore, we reveal the existence of several splice variants of the renalase gene, which potentially serve to further regulate levels of monoamine neurotransmitters in the brain. Together, our findings provide further insight into the pathways regulating monoamine neurotransmitter disposition in the brain.

Until recently, it was thought that MAO and SSAO were the only monoamine oxidases expressed in humans. The discovery of a novel FAD-dependent protein, renalase, was reported in 2005.7 Renalase was identified using an in silico approach that aimed to discover novel proteins secreted by the kidney. The renalase protein sequence contains a highly conserved N-terminal FAD-binding domain and an amine oxidoreductase domain. Renalase shares low sequence identity with MAO-A and MAO-B (17 and 20 %, respectively) but, nonetheless, its predicted secondary and tertiary structures closely resemble those of MAO-B.8 Recombinant renalase was shown to generate hydrogen peroxide in the presence of monoamines (including catecholamines), suggesting that it may share the catecholamine-degrading activity of MAO-A and B.7 This activity was greatest in the presence of dopamine (followed by adrenaline and noradrenaline),7 but it was not inhibited by MAO inhibitors, indicating differences in the possible catecholamine-degrading actions of these proteins. The renalase sequence does not contain a membrane-tethering domain, indicating that, unlike MAO-A, B and SSAO, it may be responsible for the oxidation of monoamines in the cytosol or extracellular space. Renalase was identified primarily in the human kidney and heart, and was shown to be present in the plasma of healthy individuals.7 Although it has been suggested that renalase could not contribute to catecholamine degradation in plasma,9 renalase clearly has an important role in mammalian physiology, as shown by its ability to significantly improve hemodynamic parameters in animal models.7

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Authors and Affiliations

  1. Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia

    S C Hennebry, N Eikelis, F Socratous, G Lambert & M Schlaich

  2. Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    G Desir

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  1. S C Hennebry
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  2. N Eikelis
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  3. F Socratous
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  6. M Schlaich
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Correspondence to S C Hennebry.

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Hennebry, S., Eikelis, N., Socratous, F. et al. Renalase, a novel soluble FAD-dependent protein, is synthesized in the brain and peripheral nerves. Mol Psychiatry 15, 234–236 (2010). https://doi.org/10.1038/mp.2009.74

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