Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP)

Millán, José Luis, José Luis Millán

To-date, the function of tissue-nonspecific alkaline phosphatase (TNAP) has largely been defined through studies in patients and mice affected by hypophosphatasia (HPP), a rare inborn-error-of-metabolism caused by mutation(s) in the TNAP gene (ALPL). The skeletal disease in HPP can be explained by alterations in the Pi/PPi ratio, with accumulation in the concentration of the mineralization inhibitor PPi as the culprit in preventing propagation of mineralization onto the collagenous extracellular matrix in bones and teeth. Accumulation of phosphorylated osteopontin increases the severity of HPP, at least in mice. Disruption in the metabolism of vitamin B6 leads to intracellular deficiency of pyridoxal, and this causes vitamin B6-responsive seizures in patients with the severe forms of the disease. Recent findings also implicate TNAP in the metabolism of ATP, in the production of adenosine and in the dephosphorylation of the bacterial toxin lipopolysaccharide , all molecules known to be involved in inflammation. The role of TNAP in establishing the ATP/adenosine ratio is important for purinergic signaling, and these mechanisms could be significant in determining axonal growth in the brain. Finally, the potential involvement of TNAP in dephosphorylating tau protein and its role in the pathogenesis of Alzheimer's disease is intriguing.