Regulation of the effects of antidepressants by sphingomyelin- and ceramide-controlled autophagy

通过鞘磷脂和神经酰胺控制的自噬调节抗抑郁药的作用

• 批准号: 248884541
• 负责人: Professor Dr. Erich Gulbins
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/248884541?language=en
• 关键词: Regulation; effects; antidepressants; sphingomyelin; ceramide

Our previous studies identified the acid sphingomyelinase (Asm)/ceramide system as target for antidepressants such as amitriptyline and fluoxetine. We demonstrated that amitriptyline and fluoxetine reduce Asm activity in the hippocampus and thereby increase neuronal proliferation, maturation, and survival; and improve behaviour in models of stress-induced depression. Genetic deficiency of Asm abrogates the effects of these antidepressants. Mice overexpressing Asm show constitutive changes associated with mild major depressive disorder (MDD). We showed that amitriptyline and fluoxetine induce autophagy in hippocampal neurons via a slow accumulation of sphingomyelin in lysosomes and Golgi bodies and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A (PP2A), Ulk, Beclin, PI3K/Vps34, p62 and Lc3B and thereby autophagy and the formation of autophagolysosomes. Direct inhibition of sphingomyelin synthases with D609 results in rapid accumulation of ceramide in the ER, activation of autophagy and rapid reversal of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioural changes typical of MDD. We will now investigate the hypothesis that antidepressants act by regulating the balance between ceramide in the ER, which induces autophagy and counteracts MDD, and ceramide in lysosomes, which reduces autophagy and thereby induces MDD:1. We will elucidate the role of autophagolysosome formation in the treatment of MDD (models) by using a panel of knock-out mice and transgenic mice. We will determine whether autophagolysosome formation occurs in vivo in the hippocampus, is altered upon induction of MDD, and is corrected by antidepressants; we will also determine whether autophagolysosome formation is required for the biochemical and behavioural effects of antidepressants. Molecular and cellular mechanisms by which autophagy determines the effects of antidepressants will be analyzed. 2. We will determine whether lysosomal ceramide affects autophagosome-lysosome fusion, lysosomal reformation, or both and thereby induces MDD.Ultimately, we aim to develop novel, fast-acting antidepressants by targeting sphingolipids to induce the formation of autophagolysosomes.

我们以前的研究确定了酸性鞘磷脂酶（Asm）/神经酰胺系统作为抗抑郁药如阿米替林和氟西汀的靶点。我们证明，阿米替林和氟西汀降低Asm在海马体的活性，从而增加神经元的增殖，成熟和生存，并改善应激诱导的抑郁症模型的行为。Asm的遗传缺陷消除了这些抗抑郁药的作用。过表达Asm的小鼠表现出与轻度重度抑郁症（MDD）相关的组成性变化。我们发现，阿米替林和氟西汀诱导海马神经元自噬通过缓慢积累的鞘磷脂在溶酶体和高尔基体和神经酰胺在内质网（ER）。ER神经酰胺刺激磷酸酶2A（PP 2A）、Ulk、Beclin、PI 3 K/Vps 34、p62和Lc 3B，从而刺激自噬和自噬溶酶体的形成。用D 609直接抑制鞘磷脂酰胆碱酶导致神经酰胺在ER中的快速积累、自噬的激活和应激诱导的MDD的快速逆转。抑制Beclin可阻断阿米替林和D 609的抗抑郁作用，并诱导MDD典型的细胞和行为变化。我们现在将研究抗抑郁药通过调节ER中神经酰胺（诱导自噬并抵消MDD）和溶酶体中神经酰胺（减少自噬并从而诱导MDD）之间的平衡而起作用的假设：1。我们将通过使用一组基因敲除小鼠和转基因小鼠来阐明自噬溶酶体形成在MDD（模型）治疗中的作用。我们将确定自噬溶酶体的形成是否发生在海马体内，在MDD诱导后改变，并通过抗抑郁药纠正;我们还将确定自噬溶酶体的形成是否需要抗抑郁药的生化和行为效应。将分析自噬决定抗抑郁药作用的分子和细胞机制。2.我们将确定溶酶体神经酰胺是否影响自噬体-溶酶体融合，溶酶体重组，或两者兼而有之，从而诱导MDD。最终，我们的目标是开发新的，快速作用的抗抑郁药，通过靶向鞘脂诱导自噬溶酶体的形成。