Inactivation of tissue-nonspecific alkaline phosphatase reduces phosphatidylcholine amounts in the brain of infant mice

Hypophosphatasia is a rare disease caused by dysfunctions of tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed in numerous tissues, notably the brain, and patients with hypophosphatasia exhibit neurological symptoms, including epilepsy in the most severe forms of the disease. TNAP knockout (KO) mouse models have provided a wealth of information regarding TNAP functions. Specifically, metabolomic studies focusing on the aqueous fraction of the brain of TNAP KO mice identified numerous molecules whose amounts were altered as a direct or indirect consequence of TNAP inactivation. Among these molecules, several are involved either directly (e.g., vitamin B6) or indirectly (e.g., N-acetylaspartate) in lipid metabolism. In this study, we therefore extended these investigations by examining the consequences of TNAP inactivation on the brain lipidome. We used a targeted lipidomic approach, examining four main categories of lipids: fatty acids, neutral lipids, sphingolipids and glycerophospholipids, subdivided into 16 lipid classes and amounting to 296 lipid species. Eleven lipid species showed significantly reduced amounts in the brain of TNAP KO mice. All belonged to the phosphatidylcholine class. As phosphatidylcholines are major constituents of brain cell membranes, our results suggest that hypophosphatasia could be associated with alterations in membrane structure and functions, which could contribute to the neurodevelopmental disorders associated with the disease.