Phosphatidic Acid: From Pleiotropic Functions to Neuronal Pathology

Abstract

Among the cellular lipids, phosphatidic acid (PA) is a peculiar one as it is at the same time a key building block of phospholipid synthesis and a major lipid second messenger conveying signaling information. The latter is thought to largely occur through the ability of PA to recruit and/or activate specific proteins in restricted compartments and within those only at defined submembrane areas. Furthermore, with its cone-shaped geometry PA locally changes membrane topology and may thus be a key player in membrane trafficking events, especially in membrane fusion and fission steps, where lipid remodeling is believed to be crucial. These pleiotropic cellular functions of PA, including phospholipid synthesis and homeostasis together with important signaling activity, imply that perturbations of PA metabolism could lead to serious pathological conditions. In this mini-review article, after outlining the main cellular functions of PA, we highlight the different neurological diseases that could, at least in part, be attributed to an alteration in PA synthesis and/or catabolism.

Keywords: lipid signaling; neuron; neuropathology; phosphatidic acid; phospholipase D.

Figure 1

Enzymatic routes for structural and signaling PA metabolism. PA is a major phospholipid for biosynthetic and signaling reactions. Enzymes highlighted in orange are involved in biosynthetic reactions that produce structural PA, whereas enzymes triggering the formation of signaling pools of PA are shown in purple. Enzymes responsible for PA catabolism are shown in green. ADR, Acyldihydroxyacetone-phosphate reductase; CDP, cytidyl phosphatidate; CDS, CDP-diacylglycerol (DAG) synthase; CL, cardiolipin; DHAP, dihydroxyacétone phosphate; DHAP AT, dihydroxyacétone phosphate acyltransferase; G3P, glycerol 3-phosphate; GPAT, glycerol phosphate acyltransferase; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PG, phosphatidylglycerol; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; PLA, phospholipase A; TG, triglyceride.

Figure 2

Different models for signaling activity of PA. (A) Local accumulation of PA in a single leaflet of membrane generates negative membrane curvature. (B) Local accumulation of PA generates local buildup of negative charges that recruit PA effector-containing positively charged domains. (C) PAPs transforms PA into DAG, another signaling lipid with specific activity. (D) PA stimulates the activity of phosphatidylinositol 4-phosphate 5-kinase (PI4P5K), producing PI 4,5-bisphosphate (PI(4,5)P₂), an additional important signaling lipid.