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Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.

Different tissues express different alkaline phosphatase (AP) isoforms and HPP patients' phenotypes can greatly differ in the responsiveness between tissues 1. Remarkably, comparative studies have already shown that the predominant TNAP transcript variant in bones is the same as in brain tissues 6 , which implies a common mode of TNAP function in both tissues. TNAP's most important biochemical function in bones and teeth is providing the basis for mineralization processes. The enzyme enables hydroxyapatite crystallization in bone via catalyzing the dephosphorylation of mineralization inhibitors such as inorganic pyrophosphate (PP i) and phosphorylated osteopontin 7. In the nervous system, two predominant mechanisms, the availability of vitamin B6 and alterations in purinergic signaling 8,9 , significantly influence the outcome of the disease. In case of decreased TNAP-activity, pyridoxal-5-phosphate (PLP), which is the transportable form of vitamin B6, accumulates within the serum and cannot be redistributed into the brain without dephosphorylation via TNAP. PLP is an essential enzymatic co-factor within central neurotransmitter synthesis pathways in the brain and the lack of PLP results in neurological impairment due to limited biochemical conversion 8. Additionally, TNAP enzyme supports the development and maintenance of synapse functionality and is involved in the outgrowth and myelination of neurites 10-12. Localization of TNAP within primates' brains has been described as distinct patterns within layer 4 and 5 of the cortex 13,14 and has been detected in the retina across a number of different vertebrate species 15. In mice, TNAP localization was detected predominantly in endothelial cells, primordial germ cells, pioneer growth cones, and neural precursors 16. Akp2 (the murine version of the human ALPL gene) knockout mice display reduced serum levels of alkaline phosphatase, elevated substrate levels, impaired bone mineralization, and frequently die from epileptic seizures 17,18. Due to the early lethal phenotype in mice and the lack of supplementary in vivo studies within other vertebrates, our knowledge about TNAP's interconnected functions within bone and neuronal tissues is still scarce. Due to a number of biological properties, the zebrafish (Danio rerio) has become an important vertebrate model organism for bone 19,20 and brain research 21. Along with other advantages, including low cost and easy housing of the animals, the possibility to investigate transgenic reporter lines by non-invasive in vivo monitoring and perform large scale screenings, zebrafish offer a wide repertoire of different approaches for investigation of bone and brain development 22-24. Furthermore, basic molecular pathways for vertebrate development, like bone development, are evolutionarily conserved and share common properties with other species 25,26. Consequently, a rising number of in vivo models for musculoskeletal diseases have been established in recent years 27-29 and even the molecular background of complex diseases, such...