Effects of Phospholipase A/Acyltransferase-1 (Plaat1) gene deletion on brain molecular and biochemical measures and memory

Abstract

Phospholipase A1/2 and Acyltransferase-1 (PLAAT1) is a small lipid metabolizing enzyme that possesses transacylase activity and is expressed highly in the rodent heart and brain. Recently, our lab has found that in vitro, PLAAT1 is capable of acylating monolysocardiolipin with an acyl chain donated from phosphatidylcholine acyl donors to produce cardiolipin. Cardiolipin is a glycerophospholipid that is essentially exclusive to the mitochondria and is vital for trans-membrane protein stability, inner mitochondrial membrane structure, apoptosis, and more. The de novo synthesis and acyl chain alterations (‘remodeling’) of cardiolipin are important for the health and proper functioning of cells. Previous work in our lab has demonstrated that mice deficient in Plaat1 (Plaat1-/-) had significant deficiencies in cardiac cardiolipin content, suggesting an in vivo role of PLAAT1 in cardiolipin metabolism. However, Plaat1-/- mice are poorly characterized, especially with regards to the brain, and study of this tissue, and phenotypic changes related to brain function, could help to delineate the role that PLAAT1 may serve there.

Thus, the purpose of this thesis project was to explore the effects of Plaat1-deficiency on mouse brain cardiolipin metabolism and related functions. Lipid analyses of cardiolipin, monolysocardiolipin and phosphatidylcholine revealed small, sex-specific alterations in composition but not content, while analyses of gene expression for relevant biosynthetic and remodeling enzymes exhibited significant transcriptional downregulation in female but not male Plaat1-/- brains. Immunoblotting for mitochondrial protein markers suggested changes to mitochondrial shape in female Plaat1-/- brains, while both male and female Plaat1-/- brains experienced perturbations in subunit content for complexes of the electron transport chain. Lastly, mouse anxiety and short-term memory behaviour was tested, revealing that female Plaat1-/- mice are relatively anxiolytic (relaxed), while neither male nor female Plaat1-/- mice had altered short-term memory. Taken altogether, the data collected in this project suggests that PLAAT1 acts in a tissue- and sex-specific manner for reasons that were unable to explored within the scope of this thesis project. The present thesis project demonstrates both a cellular and physiological role of PLAAT1 in the female brain, and provides a foundation from which further work on PLAAT1 can be explored. These results have implications for the interaction of sex and cardiolipin metabolism in the function of brain mitochondria and resultant behavioural outcomes.