Pivotal roles for membrane phospholipids in axonal degeneration

Membrane phospholipids are critical components of several signaling pathways. Maintained in a variety of asymmetric distributions, their trafficking across the membrane can be induced by intra-, extra-, and intercellular events. A familiar example is the externalization of phosphatidylserine from the inner leaflet to the outer leaflet in apoptosis, inducing phagocytosis of the soma. Recently, it has been recognized that phospholipids in the axonal membrane may be a signal for axonal degeneration, regeneration, or other processes. This review focuses on key recent developments and areas for ongoing investigations. KEY FACTS: Phosphatidylserine externalization propagates along an axon after axonal injury and is delayed in the Wallerian degeneration slow (Wld^S) mutant. The ATP8A2 flippase mutant has spontaneous axonal degeneration. Microdomains of axonal degeneration in spheroid bodies have differential externalization of phosphatidylserine and phosphatidylethanolamine. Phospholipid trafficking could represent a mechanism for coordinated axonal degeneration and elimination, i.e. axoptosis, analogous to apoptosis of the cell body.