Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease. Nyame et al.
Description
Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. The loss of CLN3 leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage upon CLN3 loss being robustly detected across species, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome. Mechanistically, we found that GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity and the latter of which is identified in this study. Interestingly, GPDs show more potency in inhibiting the rate-limiting lysophospholipase activity of these lipases. Consistent with our biochemical data, loss of CLN3 and sequestration of GPDs lead to the accumulation of toxic lysophospholipids, intermediates in lipid degradation, in lysosomes of CLN3-deficient cells and tissues. This work provides novel insights into lysosomal phospholipid catabolism and establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease.