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

Abstract

in women, in two cohorts of older normal individuals. These risk alleles have previously been associated with schizophrenia, bipolar disorder, and social and physical anhedonia, mainly in females. 1,7 Reports suggest that heritability of neuroticism, anxiety and depression is higher in females than in males, and that the genes involved differ between men and women. [8][9][10] We tested SNPs and models specifically chosen on the basis of earlier evidence, and hence do not believe that stringent multiple testing corrections are appropriate, but these results need to be replicated in other suitable cohorts before variation in DISC1 is fully accepted as contributing to normal variation in neuroticism and mood. Conflict of interestThe authors declare no conflict of interest. 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's 6 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 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 This activity was greatest in the presence of dopamine (followed by adrenaline and noradrenaline), 7 but it was not inhibited by MAO inhibitors, indicating differen...

Is Renalase a Novel Player in Catecholaminergic Signaling? The Mystery of the Catalytic Activity of an Intriguing New Flavoenzyme

“…Widespread transcription of the human relanase gene is also confirmed by 6 microarray data [21] and Whole Transcriptome Next-Generation Sequencing (RNA-Seq) [22]. Renalase 1 is the only isoform apparently detected in blood plasma and urine and it represents the major isoform in all tissues tested (kidney, heart, skeletal muscle, liver, testicle, hypothalamus, adrenal gland) [1,19]. Transcripts encoding renalase 2 and the two shortest variants (AK296262 and BX648154), although at lower levels than renalase 1 mRNA, were observed in all samples examined, while no renalase 2 transcript was detected in the hypothalamus [19].…”

“…In addition to kidney and myocardium [1], renalase was found in forearm vein and artery, renal vein and artery, ureter, median nerve, hypothalamus, pons, medulla oblongata, cerebellum, pituitary grand, cortex, and spinal cord [19]. In the kidneys, renalase was shown to be present in glomeruli and proximal tubules [1].…”

“…Different mRNA transcripts of RNLS have been detected and sequenced, highlighting the existence of protein variants originating from alternative splicing [8,18,19]. Besides the aforementioned renalase1 (NP_001026879), a second annotated protein isoform exists (renalase 2, NP_060833), with a slightly shorter polypeptide chain (315 residues) and a different sequence in its C-terminal region.…”

“…Renalase 1 is the only isoform apparently detected in blood plasma and urine and it represents the major isoform in all tissues tested (kidney, heart, skeletal muscle, liver, testicle, hypothalamus, adrenal gland) [1,19]. Transcripts encoding renalase 2 and the two shortest variants (AK296262 and BX648154), although at lower levels than renalase 1 mRNA, were observed in all samples examined, while no renalase 2 transcript was detected in the hypothalamus [19]. A renalase concentration of 0.1 mg per gram wet tissue has been estimated in the kidneys by immunoblotting [10].…”

“…In the most comprehensive study on the pattern of RNLS expression published so far, autoptic human tissues samples known to express MAOs have been analyzed both by immunoblotting using an anti-renalase monoclonal antibody and by reverse transcriptase polymerase chain reaction [19]. In addition to kidney and myocardium [1], renalase was found in forearm vein and artery, renal vein and artery, ureter, median nerve, hypothalamus, pons, medulla oblongata, cerebellum, pituitary grand, cortex, and spinal cord [19].…”