Plasmosphingomyelin has been found to regulate circadian behavior in Drosophila

The Tax Light Thick Research Group of the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences used Drosophila as a model to explore and confirm the role of sphingomylin content in the regulation of drosophilia in the regulation of drosophilia biorhythm and lifespan through systematic research such as genetic screening, lipid/metabolomics, proteomics and other systematic studies, and the research results were recently published online in the National Science Review.

The circadian clock controls the daily fluctuations of metabolism, eating-fasting cycles, and sleep-wake activity, and plays a key role in aging and various metabolic disorders. Fruit flies are key model organisms for studying circadian rhythm regulation, and a large number of characteristic clock genes have been identified through genetic screening.

Sphingomyelin (SM; In Drosophila is ceramide ethanolamine phosphate, CPE) is one of the main sphingolipid components that form the plasma membrane of animal cells and is widely distributed in all tissues, especially in the central nervous system. The research team’s previous lipidomics work found huge differences in the biorhythm of sphingomyelin in individual plasma, but the mechanistic link between sphingolipids and circadian regulation has not been known to date.

The researchers first constructed various gene mutants related to cpe biosynthesis and metabolism in Drosophila through CRISPR/Cas9 and combined with gene manipulation expression, making it clear that CPE affects the maintenance of circadian rhythms, and found that CPE deficiency can lead to arrhythmias and shorten lifespan, while increasing CPE restores Drosophila rhythm and greatly prolongs its lifespan. Tissue-specific studies have found that decreased CPE levels in astrocyte-like glial cells (ALG) are the basis for circadian rhythm disturbances in cpes mutants.

Metabolomics studies have shown that a significant increase in large amounts of purines (such as adenosine) and amino acid metabolism-related substances (such as kynulic acid) found in the brains of glial-specific knock-down CPE flies, extracellular purine release may help regulate glutamate presynaptic release, and the increase in urynine as a glutamate antagonist may mean compensatory responses to prevent glutamate-induced excitatory toxic damage. Finally, through extensive genetic screening, it was found that the trans synaptic dysregulation of abnormal rhythm activity in Drosophila was mainly attributed to abnormal glutamate signaling and changes in glutamate consumption, and the reduction of CPE led to abnormal glial glutamate signaling and disrupted circadian rhythms, which relied on the endogenous abundance of CPE, and arrhythmic movement in the context of CPES1 mutations could be salvaged by the expression of their respective synthases to restore endogenous sphingomyelin (CPE or SM).

In summary, the study points out that plasma membrane sphingomyelin plays a crucial role in regulating the circadian behavior of Drosophila, mainly through glial cell coupling to regulate synaptic glutamate homeostasis, and the functional region-specific increase of membrane lipids is conducive to circadian rhythm regulation and prolonged life.

Schematic model of abnormal presynaptic glutamate signaling under glial-specific cpes knockout Courtesy of the authors

Chen Xiupeng and Li Jie, phD students of the Tax Guanghou Research Group, are the co-first authors of the paper, and Researcher Tax Guanghou and Dr. Lam Sin Man are the co-corresponding authors of this paper. The research was funded by the National Natural Science Foundation of China and the Key R&D Program of the Ministry of Science and Technology. (Source: China Science Daily Feng Lifei)

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