Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo.

IF 2.9 4区 医学 Q2 PHYSIOLOGY
Maximilian Schiller, Gregory C Wilson, Simone Keitsch, Matthias Soddemann, Barbara Wilker, Michael J Edwards, Norbert Scherbaum, Erich Gulbins
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Abstract

Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.

磷脂酸参与体外和体内神经元自噬的调节。
重度抑郁障碍(MDD)是一种常见的严重精神疾病,它不仅会导致各种神经精神症状,而且不幸的是,在相当大比例的病例中还会导致自杀。抑郁症的发病机制仍有待明确。我们之前已经证明,多发性硬化症患者血浆中的神经酰胺会增加。在通过皮质酮治疗或施加慢性不可预测压力诱导的 MDD 小鼠模型中,血浆中增加的神经酰胺也会增加,并导致海马内皮细胞中的磷脂酶 D 受抑制,海马中的磷脂酸水平降低。在这里,我们证明了皮质酮处理 PC12 细胞会导致细胞自噬减少,而用磷脂酸处理则可纠正这种情况。在体内,用皮质酮或慢性不可预知应激处理小鼠也会减少海马神经元的自噬。在这些 MDD 小鼠模型中,静脉注射磷脂酸后自噬功能恢复正常。为了确定磷脂酸在神经元中的作用靶点,我们证实皮质酮会降低 PC-12 细胞和小鼠海马中神经节苷脂 GM1 的水平,而处理细胞或给小鼠静脉注射磷脂酸可使这一水平恢复正常。施用 GM1 还能使培养神经元的自噬正常化。磷脂酸和 GM1 可纠正应激诱导的小鼠实验性 MDD 行为改变,即主要是焦虑和失神。我们的数据表明,磷脂酸可通过 GM1 调节神经元的自噬。
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来源期刊
CiteScore
8.80
自引率
2.20%
发文量
121
审稿时长
4-8 weeks
期刊介绍: Pflügers Archiv European Journal of Physiology publishes those results of original research that are seen as advancing the physiological sciences, especially those providing mechanistic insights into physiological functions at the molecular and cellular level, and clearly conveying a physiological message. Submissions are encouraged that deal with the evaluation of molecular and cellular mechanisms of disease, ideally resulting in translational research. Purely descriptive papers covering applied physiology or clinical papers will be excluded. Papers on methodological topics will be considered if they contribute to the development of novel tools for further investigation of (patho)physiological mechanisms.
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