生物
分解代谢
巴顿病
磷脂
细胞生物学
溶酶体
生物化学
新陈代谢
酶
基因
膜
作者
Kwamina Nyame,Andy Hims,Aya Aburous,Nouf N. Laqtom,Wentao Dong,Uche N. Medoh,Julia C. Heiby,Jie Xiong,Alessandro Ori,Monther Abu-Remaileh
标识
DOI:10.1016/j.molcel.2024.02.006
摘要
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.
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