Axonal degeneration induces distinct patterns of phosphatidylserine and phosphatidylethanolamine externalization

Abstract

Axonal degeneration is a common feature of multiple neurodegenerative diseases, yet the mechanisms underlying its various manifestations are incompletely understood. We previously demonstrated that axonal degeneration is associated with externalization of phosphatidylserine (PS), which precedes morphological evidence of degeneration, is redox-sensitive, and is delayed in Wallerian degeneration slow (WldS) mutant animals. Phosphatidylethanolamine (PE) is the other major membrane phospholipid in the inner leaflet of the cell membrane, and given that PS signals apoptosis, phagocytosis, and degeneration, we hypothesized that PS and PE membrane dynamics play distinct roles in axonal degeneration. To test this hypothesis, axonal degeneration was induced with calcium ionophores in postnatal rat retinal ganglion cells, and PS- and PE-specific fluorescent probes used to measure their externalization over time. In untreated cells, cell-surface PS was prominent in the cell body alone. Elevation of intracellular calcium with calcium ionophores resulted in significantly increased levels of PS externalization in the cell body, axon, and axon growth cone. Unlike PS, cell-surface PE was diffusely distributed in untreated cells, with comparable levels across the soma, axons, and axon terminals. After exposure to calcium ionophores, PE externalization significantly increased in the cell body and axon. Elevated intracellular calcium also resulted in the formation of axonal blebs which exclusively contained externalized PS, but not PE. Together, these results indicated distinct patterns of externalized PS and PE in normal and degenerating neurons, suggesting a differential role for these phospholipids in transducing neuronal injury.

In Vivo Imaging of Secondary Neurodegeneration Associated With Phosphatidylserine Externalization Along Axotomized Axons

“… 20 , 21 It is also possible that the spread of axonal injury is related to PS externalization, which is an “eat-me” signal for macrophages or other phagocytic cells. 22 , 23 An activation of phagocytosis of primarily injured axons could result in a bystander effect for adjacent axons within the same axonal bundle.…”

Preparation of genetically or chemically engineered exosomes and their therapeutic effects in bone regeneration and anti-inflammation

“…Recent studies have shown that phosphatidylserine is a lipid in cells exposed to the surface after axonal injury (Faris et al, 2021). Phosphatidylserine is essential in identifying and promoting axon fusion and regeneration after injury…”

Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves

“…The phospholipid phosphatidylserine (PS), which is normally present primarily in the inner leaflet of the plasma membrane and excluded from the outer leaflet of healthy neurons 50 , is exposed on the external leaflet of the axon membrane during bioenergetic stress 21 . Moreover, exposed PS is concentrated on axonal swellings 22,51 . Up until this point, nearly all studies on PS exposure on compromised axons have been done in acute injury conditions [21][22][23]51 .…”

“…Moreover, exposed PS is concentrated on axonal swellings 22,51 . Up until this point, nearly all studies on PS exposure on compromised axons have been done in acute injury conditions [21][22][23]51 . Here we leveraged our dKO model to examine whether PS exposure also occurs with chronic SARM1 activation.…”