Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J Neurochem. 2022 Nov;163(4):357-369. doi: 10.1111/jnc.15708. Epub 2022 Oct 24.
Major depressive disorder (MDD) is a severe disease of unknown pathogenesis with a lifetime prevalence of ~10%. Therapy requires prolonged treatment that often fails. We have previously demonstrated that ceramide levels in the blood plasma of patients and in mice with experimental MDD are increased. Neutralization of blood plasma ceramide prevented experimental MDD in mice. Mechanistically, we demonstrated that blood plasma ceramide accumulated in endothelial cells of the hippocampus, inhibited phospholipase D (PLD) and thereby decreased phosphatidic acid in the hippocampus. Here, we demonstrate that phosphatidic acid binds to and controls the activity of phosphotyrosine phosphatase (PTP1B) in the hippocampus and thus determines tyrosine phosphorylation of a variety of cellular proteins including TrkB. Injection of PLD, phosphatidic acid, or inhibition of PTP1B abrogated MDD and normalized cellular tyrosine phosphorylation, including phosphorylation of TrkB and neurogenesis in the hippocampus. Most importantly, these treatments also rapidly normalized behavior of mice with experimental MDD. Since phosphatidic acid binds to and inhibits PTP1B, the lack of phosphatidic acid results in increased activity of PTP1B and thereby in reduced tyrosine phosphorylation of TrkB and other cellular proteins. Thus, our data indicate a novel pathogenetic mechanism of and a rapidly acting targeted treatment for MDD.
重度抑郁症（MDD）是一种病因不明的严重疾病，终身患病率约为 10%。治疗需要长期进行，而且常常无效。我们之前的研究表明，抑郁症患者和实验性 MDD 小鼠的血浆神经酰胺水平升高。中和血浆神经酰胺可预防实验性 MDD 发生。从机制上看，我们证明了血浆神经酰胺在海马内皮细胞中积累，抑制了磷脂酶 D（PLD），从而降低了海马中的磷酸脂酸。在这里，我们证明了磷酸脂酸结合并控制了海马中的磷酸酪氨酸磷酸酶（PTP1B）的活性，从而决定了包括 TrkB 在内的多种细胞蛋白的酪氨酸磷酸化。PLD、磷酸脂酸的注射或 PTP1B 的抑制作用可消除 MDD 并使海马中的细胞酪氨酸磷酸化正常化，包括 TrkB 的磷酸化和神经发生。最重要的是，这些治疗方法还能迅速使实验性 MDD 小鼠的行为正常化。由于磷酸脂酸结合并抑制 PTP1B，缺乏磷酸脂酸会导致 PTP1B 活性增加，从而导致 TrkB 和其他细胞蛋白的酪氨酸磷酸化减少。因此，我们的数据表明了 MDD 的一种新的发病机制和一种快速作用的靶向治疗方法。
