PDF(Pubmed)
Abstract：
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.
摘要：
Batten病,儿童神经变性最普遍的形式，是由CLN3基因突变引起的,编码溶酶体跨膜蛋白。CLN3损失导致甘油磷酸二酯（GPDs）的显著积累，溶酶体中甘油磷脂分解代谢的最终产物。尽管在CLN3损失时观察到了GPD的储存，GPDs在神经病理学中的作用尚不清楚.这里,我们证明,使用人细胞系和小鼠模型,GPDs可作为溶酶体中甘油磷脂分解代谢的有效抑制剂.机械上,GPDs结合并竞争性抑制溶酶体磷脂酶PLA2G15和PLBD2，我们确定它们具有磷脂酶B活性。GPD有效抑制这些磷脂酶的限速溶血磷脂酶活性。始终如一，CLN3缺陷细胞和组织的溶酶体积累毒性溶血磷脂。我们的工作表明，巴顿病中的储存物质直接破坏溶酶体脂质稳态，提示GPD清除是这种致命疾病的潜在治疗方法。
