Abstract：
Mutations in the DDHD2 (DDHD domain containing 2) gene cause autosomal recessive spastic paraplegia type 54 (SPG54), a rare neurodegenerative disorder characterized by the early childhood onset of progressive spastic paraplegia. DDHD2 is reported as the principal brain triacylglycerol (TAG) lipase whose dysfunction causes massive lipid droplet (LD) accumulation in the brains of SPG54 patients. However, the precise functions of DDHD2 in regulating LD catabolism are not yet fully understood. In a recent study, we demonstrate that DDHD2 interacts with multiple members of the Atg8-family proteins (MAP1LC3/LC3s, GABARAPs), which play crucial roles in lipophagy. DDHD2 possesses two LC3-interacting region (LIR) motifs that contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a compound that tethers LC3 to LDs to enhance their macroautophagic/autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide insights into the dual functions of DDHD2 as a TAG lipase and cargo receptor for lipophagy in neuronal LD catabolism, and also suggest a potential therapeutic approach for treating SPG54 patients.
摘要：
DDHD2（含DDHD结构域2）基因突变导致常染色体隐性遗传性痉挛性截瘫54型（SPG54），一种罕见的神经退行性疾病，其特征是儿童早期进行性痉挛性截瘫。据报道，DDHD2是主要的脑三酰甘油（TAG）脂肪酶，其功能障碍会导致SPG54患者大脑中大量脂滴（LD）积累。然而,DDHD2在调节LD分解代谢中的确切功能尚未完全了解。在最近的一项研究中,我们证明DDHD2与Atg8家族蛋白的多个成员（MAP1LC3/LC3s，GABARAP),在吸脂症中起着至关重要的作用。DDHD2具有两个LC3相互作用区（LIR）基序，这些基序有助于其LD消除活性。此外，DDHD2增强LC3B和LD之间的共定位以促进脂质吞噬。LD·ATTEC,一种将LC3束缚到LD以增强其大自噬/自噬清除的化合物，有效地抵消DDHD2缺乏诱导的LD积累。这些发现为DDHD2作为TAG脂肪酶和货物受体在神经元LD分解代谢中吸脂的双重功能提供了见解，并提出了治疗SPG54患者的潜在治疗方法。
