The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase
The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase
复制标题
DOI：
10.1073/pnas.1413706111
复制
发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Inloes, Jordon M.;Hsu, Ku-Lung;Cravatt, Benjamin F.
复杂性遗传性痉挛性截瘫（HSP）是一种遗传性疾病，导致下肢痉挛和虚弱和智力残疾。丝氨酸水解酶DDHD 2的突变是隐性复合HSP的致病基础。DDHD 2在体外表现出磷脂酶活性，但其内源性底物和生化功能尚不清楚。在这里，我们报告了DDHD 2（-/-）小鼠和选择性体内活性DDHD 2抑制剂的开发，以及它们与基于质谱的脂质组学结合使用，以发现DDHD 2调节脑甘油三酯（三酰甘油，或TAG）。DDHD 2（-/-）小鼠在中枢神经系统中显示出年龄依赖性TAG升高，但在几种外周组织中没有。大的脂滴在DDHD 2（-/-）脑中积聚，主要定位于神经元的细胞内区室。这些代谢变化伴随着运动和认知功能的损害。重组DDHD 2显示TAG水解酶活性，并且TAG在用选择性DDHD 2抑制剂亚慢性治疗的野生型小鼠的脑中积累。这些发现共同表明，中枢神经系统具有代谢TAG的专门途径，其破坏导致神经元中的大量脂质积累和复杂HSP综合征。
Complex hereditary spastic paraplegia (HSP) is a genetic disorder that causes lower limb spasticity and weakness and intellectual disability. Deleterious mutations in the poorly characterized serine hydrolase DDHD2 are a causative basis for recessive complex HSP. DDHD2 exhibits phospholipase activity in vitro, but its endogenous substrates and biochemical functions remain unknown. Here, we report the development of DDHD2(-/-) mice and a selective, in vivo-active DDHD2 inhibitor and their use in combination with mass spectrometry-based lipidomics to discover that DDHD2 regulates brain triglycerides (triacylglycerols, or TAGs). DDHD2(-/-) mice show age-dependent TAG elevations in the central nervous system, but not in several peripheral tissues. Large lipid droplets accumulated in DDHD2(-/-) brains and were localized primarily to the intracellular compartments of neurons. These metabolic changes were accompanied by impairments in motor and cognitive function. Recombinant DDHD2 displays TAG hydrolase activity, and TAGs accumulated in the brains of wild-type mice treated subchronically with a selective DDHD2 inhibitor. These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome.