Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis.
J. Neurochem.. 2017-03-01; 140(6): 919-940
DOI: 10.1111/jnc.13950
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Cruz T(1), Gleizes M(2), Balayssac S(1), Mornet E(3), Marsal G(2), Millán JL(4), Malet-Martino M(1), Nowak LG(2), Gilard V(1), Fonta C(2).
Author information:
(1)Groupe de RMN Biomédicale, Laboratoire SPCMIB (CNRS UMR 5068), Université Paul Sabatier, Université de Toulouse, Toulouse Cedex, France.
(2)Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549, Toulouse, France.
(3)Unité de Génétique Constitutionnelle Prénatale et Postnatale, Service de Biologie, Centre Hospitalier de Versailles, Le Chesnay, France.
(4)Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
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 used 1 H- and 31 P 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.
© 2017 International Society for Neurochemistry.