Deleterious mutations in the serine lipase DDHD2 are a causative basis of complex hereditary spastic paraplegia (HSP, subtype SPG54) in humans. We recently found that DDHD2 is a principal triglyceride hydrolase in the central nervous system (CNS) and that genetic deletion of this enzyme in mice leads to ectopic lipid droplet (LD) accumulation in neurons throughout the brain. Nonetheless, how HSP-related mutations in DDHD2 relate to triglyceride metabolism and LD formation remains poorly understood. Here, we have characterized a set of HSP-related mutations in DDHD2 and found that they disrupt triglyceride hydrolase activity in vitro and impair the capacity of DDHD2 to protect cells from LD accumulation following exposure to free fatty acid, an outcome that was also observed with a DDHD2-selective inhibitor. We furthermore isolated and characterized LDs from brain tissue of DDHD2-/- mice, revealing that they contain both established LD-associated proteins identified previously in other organs and CNS-enriched proteins, including several proteins with genetic links to human neurological disease. These data, taken together, indicate that the genetic inactivation of DDHD2, as caused by HSP-associated mutations, substantially perturbs lipid homeostasis and the formation and content of LDs, underscoring the importance of triglyceride metabolism for normal CNS function and the key role that DDHD2 plays in this process.

中文翻译：

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痉挛性截瘫相关甘油三酸酯水解酶DDHD2对脂质液滴形成和含量的功能性贡献。

丝氨酸脂肪酶DDHD2中的有害突变是人类复杂遗传性痉挛性截瘫（HSP，SPG54亚型）的致病基础。我们最近发现DDHD2是中枢神经系统（CNS）中的主要甘油三酸酯水解酶，并且该酶在小鼠中的基因缺失导致异位脂质滴（LD）在整个大脑神经元中积累。然而，关于DDHD2中HSP相关的突变与甘油三酸酯代谢和LD形成的关系仍知之甚少。在这里，我们已经对DDHD2中一系列与HSP相关的突变进行了表征，发现它们在体外破坏了甘油三酸酯水解酶的活性，并削弱了DDHD2保护细胞免受暴露于游离脂肪酸后LD积累的能力。 DDHD2选择性抑制剂。我们进一步从DDHD2-/-小鼠的脑组织中分离并鉴定了LDs，发现它们既包含先前在其他器官中鉴定出的已建立的LD相关蛋白，又包含富含CNS的蛋白，包括与人类神经系统疾病具有遗传联系的几种蛋白。这些数据加在一起表明，由HSP相关突变引起的DDHD2的遗传失活，极大地干扰了脂质稳态以及LD的形成和含量，从而突出了甘油三酸酯代谢对于正常CNS功能的重要性以及DDHD2的关键作用。在这个过程中发挥作用。包括几种与人类神经系统疾病有遗传联系的蛋白质。这些数据加在一起表明，由HSP相关突变引起的DDHD2的遗传失活，极大地干扰了脂质稳态以及LD的形成和含量，从而突出了甘油三酸酯代谢对于正常CNS功能的重要性以及DDHD2的关键作用。在这个过程中发挥作用。包括几种与人类神经系统疾病具有遗传联系的蛋白质。这些数据加在一起表明，由HSP相关突变引起的DDHD2的遗传失活，极大地干扰了脂质稳态以及LD的形成和含量，从而突出了甘油三酸酯代谢对于正常CNS功能的重要性以及DDHD2的关键作用。在这个过程中发挥作用。