Rhein Cosima, Zoicas Iulia, Marx Lena M, Zeitler Stefanie, Hepp Tobias, von Zimmermann Claudia, Mühle Christiane, Richter-Schmidinger Tanja, Lenz Bernd, Erim Yesim, Reichel Martin, Gulbins Erich, Kornhuber Johannes
Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany.
Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany.
Int J Mol Sci. 2021 May 27;22(11):5700. doi: 10.3390/ijms22115700.
Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of , which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.
重度抑郁症（MDD）是一种严重的精神疾病，其主要症状为情绪低落、缺乏动力、愉悦感和快感。最近，酸性鞘磷脂酶（ASM）/神经酰胺系统被认为与MDD的发病机制有关。ASM是一种溶酶体糖蛋白，它催化膜的丰富成分鞘磷脂水解为生物活性鞘脂神经酰胺，后者影响信号通路。几种常见的抗抑郁药物可抑制ASM活性。人和小鼠研究已证实，ASM活性增加和神经酰胺水平升高与MDD相关。为了确定用于治疗监测的分子标志物，我们在原代细胞培养模型、一项小鼠研究以及一项针对未治疗的MDD患者在抗抑郁治疗前后的人体研究中，调查了编码ASM的 的mRNA表达。我们的细胞培养研究表明，一种常见的抗抑郁药物在酶水平以及转录水平均抑制ASM活性。在具有类似抑郁行为的转基因小鼠品系中，用一种常见的抗抑郁药物治疗后，背侧海马组织中的mRNA表达显著降低。大规模人体研究表明，未治疗的MDD患者在抗抑郁治疗后，mRNA表达显著下降。这项转化研究表明，mRNA表达可作为MDD治疗和依从性监测的分子标志物。
