Modulation of Chondroitin Sulfation by Lithium-Inhibited Bisphosphate Nucleotidase 2

Abstract

Golgi-resident bisphosphate nucleotidase 2 (BPNT2) is a member of a family of magnesium-dependent phosphatases that are directly inhibited by lithium, the first-line medication for bipolar disorder. BPNT2 is localized to the Golgi, where it metabolizes phosphoadenosine phosphate (PAP), the by-product of glycosaminoglycan (GAG) sulfation reactions. Knockout of Bpnt2 in mice leads to skeletal abnormalities due to impaired GAG sulfation, especially chondroitin-4-sulfation, which is critical for proper extracellular matrix development in the skeletal and nervous systems. In this work, we demonstrate that the catalytic activity of BPNT2 is necessary for GAG sulfation, and that lithium impairs sulfation in vitro in a BPNT2-dependent manner. Previous work has demonstrated the importance of chondroitin sulfation in the brain, as chondroitin-4-sulfate is a major component of perineuronal nets (PNNs), a specialized neuronal extracellular matrix which mediates synaptic plasticity and regulates certain behaviors. We hypothesized that the loss of BPNT2 in the nervous system would decrease chondroitin-4-sulfation in the brain. We utilized Cre-lox breeding to knockout Bpnt2 specifically in the nervous system using Bpnt2 floxed (fl/fl) animals and a Nestin-driven Cre recombinase. Interestingly, these changes were not correlated with gross alterations in PNNs or behavioral abnormalities. Taken together, this work demonstrates that the catalytic activity of an enzyme potently inhibited by lithium can modulate GAG sulfation and therefore extracellular matrix composition both in vitro and in the brain, suggesting that lithium-mediated inhibition of BPNT2 in the nervous system warrants further investigation.