title: Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis.
abstract: Tissue non-specific alkaline phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However, TNAP's role in the nervous system remains poorly understood. To investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used1H- and31P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well-described model of infantile HPP. Among 39 metabolites identified in brain extracts of 1-week-old animals, eight displayed significantly different concentration in Akp2-/-compared to Akp2+/+and Akp2+/-mice: cystathionine, adenosine, GABA, methionine, histidine, 3-methylhistidine, N-acetylaspartate (NAA), and N-acetyl-aspartyl-glutamate, with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto-nucleotide levels and of pyridoxal phosphate-dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP.
authors.affiliation: Groupe de RMN Biomédicale, Laboratoire SPCMIB (CNRS UMR 5068), Université Paul Sabatier, Université de Toulouse, Toulouse Cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cruz
authors.affiliation: Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549, Toulouse, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Gleizes
authors.affiliation: Groupe de RMN Biomédicale, Laboratoire SPCMIB (CNRS UMR 5068), Université Paul Sabatier, Université de Toulouse, Toulouse Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Balayssac
authors.affiliation: Unité de Génétique Constitutionnelle Prénatale et Postnatale, Service de Biologie, Centre Hospitalier de Versailles, Le Chesnay, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Mornet
authors.affiliation: Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549, Toulouse, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Marsal
authors.affiliation: Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Groupe de RMN Biomédicale, Laboratoire SPCMIB (CNRS UMR 5068), Université Paul Sabatier, Université de Toulouse, Toulouse Cedex, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Malet-Martino
authors.affiliation: Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549, Toulouse, France.
authors.forename: Lionel G
authors.initials: LG
authors.lastname: Nowak
authors.affiliation: Groupe de RMN Biomédicale, Laboratoire SPCMIB (CNRS UMR 5068), Université Paul Sabatier, Université de Toulouse, Toulouse Cedex, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gilard
authors.affiliation: Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549, Toulouse, France.
authors.forename: Caroline
authors.identifier: 0000-0001-6326-4044
authors.initials: C
authors.lastname: Fonta
mesh_terms: D000469:Alkaline Phosphatase / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007014:Hypophosphatasia / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout
chemical_list: C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase
keywords: MSCA-1; cystathionine; neuron; nucleotide; pyridoxal phosphate; tissue non-specific alkaline phosphatase