Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease

Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work 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. [Display omitted] •Excess GPDs in CLN3-deficient lysosomes reduce lysosomal phospholipase activity•PLA2G15 and PLBD2 are major lysosomal phospholipases with phospholipase B activity•GPDs bind and competitively inhibit PLA2G15 and PLBD2 activity•CLN3-deficient lysosomes accumulate lysophospholipids via GPD-mediated inhibition Nyame et al. reveal a pathological role for the Batten disease storage metabolites glycerophosphodiesters (GPDs) in the lysosome. GPDs bind and inhibit key lysosomal phospholipases, leading to accumulation of lysophospholipids, intermediates in phospholipid degradation known for their toxicity. Additionally, they comprehensively characterize lysosomal phospholipid catabolism, a pathway crucial in several biological processes.