Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
Lundbeck, La Jolla, California 92121, United States.
Biochemistry. 2020 May 19;59(19):1793-1799. doi: 10.1021/acs.biochem.0c00292. Epub 2020 May 4.
PHARC (polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and cataract) is a human neurological disorder caused by deleterious mutations in the gene, which encodes an integral membrane lyso-phosphatidylserine (lyso-PS) lipase. Pharmacological or genetic disruption of ABHD12 leads to higher levels of lyso-PS lipids in human cells and the central nervous system (CNS) of mice. ABHD12 loss also causes rapid rewiring of PS content, resulting in selective increases in the level of arachidonoyl (C20:4) PS and decreases in the levels of other PS species. The biochemical basis for ABHD12-dependent PS remodeling and its pathophysiological significance remain unknown. Here, we show that genetic deletion of the lysophospholipid acyltransferase LPCAT3 blocks accumulation of brain C20:4 PS in mice lacking ABHD12 and concurrently produces hyper-increases in the level of lyso-PS in these animals. These lipid changes correlate with exacerbated auditory dysfunction and brain microgliosis in mice lacking both ABHD12 and LPCAT3. Taken together, our findings reveal that ABHD12 and LPCAT3 coordinately regulate lyso-PS and C20:4 PS content in the CNS and point to lyso-PS lipids as the likely bioactive metabolites contributing to PHARC-related neuropathologies.
PHARC（多发性神经病、听力损失、小脑共济失调、视网膜色素变性和白内障）是一种人类神经紊乱疾病，由基因中的有害突变引起，该基因编码一种完整的膜溶磷脂酰丝氨酸（lyso-PS）脂肪酶。ABHD12 的药理学或遗传破坏导致人类细胞和小鼠中枢神经系统（CNS）中溶酶体 PS 脂质水平升高。ABHD12 的缺失还导致 PS 含量的快速重布线，导致花生四烯酸酰基（C20:4）PS 的水平选择性增加，而其他 PS 物种的水平降低。ABHD12 依赖性 PS 重塑的生化基础及其病理生理意义尚不清楚。在这里，我们表明，缺失溶脂酰基转移酶 LPCAT3 的基因缺失会阻止缺乏 ABHD12 的小鼠大脑中 C20:4 PS 的积累，同时在这些动物中导致溶酶体 PS 水平的急剧增加。这些脂质变化与缺乏 ABHD12 和 LPCAT3 的小鼠的听觉功能障碍和大脑小胶质细胞增生加剧相关。总之，我们的发现表明 ABHD12 和 LPCAT3 协调调节中枢神经系统中的溶酶体 PS 和 C20:4 PS 含量，并指出溶酶体 PS 脂质可能是导致 PHARC 相关神经病理学的生物活性代谢物。
