Impaired membrane lipid homeostasis in schizophrenia.

Li M, Gao Y, Wang D, Hu X, Jiang J, Qing Y, Yang X, Cui G, Wang P, Zhang J, Sun L, and Wan C. (2022) Impaired membrane lipid homeostasis in schizophrenia. Schizophrenia Bulletin

Schizophrenia (SCZ) is a mental disorder characterized by an abnormal interpretation of reality which manifests through delusions, hallucinations, and disorganized thoughts, behaviour, and speech. These symptoms are caused by abnormalities in development, inflammatory responses, and energy metabolism. Although the etiology is not fully known, it has been found that environmental and genetic factors play a role in the pathology. Interestingly, many years ago it was also found that there are abnormal phospholipid dissociation processes in cell membranes of people with SCZ, suggesting that SCZ could be a disorder caused by abnormal membrane phospholipids. Plasmalogens are a class of phospholipid that contain a vinyl-ether bond at the sn-1 position on the glycerol backbone, causing these lipids to have a compact structure. This conformation gives plasmalogens roles in membrane structure and fluidity, protecting against oxidative stress, and vesicular fusion. Due to the implication of lipid changes in people with SCZ, Li et al were interested in investigating the lipidome of erythrocyte membranes in SCZ patients and healthy controls and how this affects oxidative stress levels.

To study lipidome differences in SCZ, erythrocytes were collected from 80 subjects with SCZ and 40 healthy controls and were analyzed using ultra-high performance liquid chromatography (UHPLC-MS). Multivariate analyses of 812 lipid classes including phosphatidyl ethanolamines, phosphatidyl cholines, phosphatidylserines, phosphatidylinositols, sphingomyelins, ceramides, triacylglycerols, diacylglycerols, lysophosphatidylethanolamines, lysophosphatidylcholines, and lysophosphatidylserines demonstrated that there were significant differences between the two sample groups. Of the 812, 387 lipids were found to be different between the SCZ and healthy control groups, and 244 of these were significantly reduced in SCZ. Included in the 244 that were decreased, 154 were ethanolamine plasmalogens and choline plasmalogens. Interestingly, ethanolamine plasmalogen 18:3/20:4 was able to effectively distinguish between patients with SCZ and the healthy controls, making it a potential biomarker of SCZ.

To determine if oxidative stress levels are different in people with SCZ compared to the control group, changes in oxidized lipids were analyzed. Sixty-seven oxidative lipids were detected and 44.8% were significantly increased in the SCZ subjects. As well, total ethanolamine plasmalogen concentrations were significantly lower in people with SCZ. Plasma levels of 4-hydroxynonenoic acid (4-HNE), a lipid peroxide, were higher in SCZ patients than healthy controls, but superoxide dismutase (SOD), an antioxidant enzyme that can scavenge reactive oxygen species (ROS), was found to be decreased in the patients with SCZ. With the combination of reduced plasmalogens and SOD activity and increased 4-HNE activity, it is unsurprising that there is a significant increase in oxidized lipids in this group, also indicating an increase in oxidative stress in people with SCZ.

Changes in lipid levels had been observed in clinical stages of psychosis and suggested that membrane metabolism may be dysregulated in SCZ. Because of this and other work that indicated a reduction in plasmalogens in SCZ, Li et al wanted to determine how the lipidome and oxidative stress levels differ between SCZ and healthy controls. Out of 812 lipids studied 387 were significantly different between the groups with 244 being reduced in the erythrocyte membranes of patients with SCZ. This was associated with a reduction in plasmalogens and SOD, as well as an increase in 4-HNE, together resulting in an increase in oxidative stress. A potential biomarker for SCZ was also discovered, where ethanolamine plasmalogen 18:3/20:4 was able to distinguish between people with SCZ and healthy controls. The authors suggest that the change in lipid levels could be caused by reduced levels of phospholipid precursors in the brains of people with SCZ, seen in previous studies, which would reduce the levels of phosphatidyl ethanolamines and phosphatidyl cholines. Another reason they propose based on the work in this paper is that membrane homeostasis is affected by dysregulation of phospholipid remodeling and increased oxidative stress. Further work confirming the biomarker in a larger cohort would be interesting, as well as continuing to study the lipidome of people with SCZ for future therapies.