Regulation of degenerative spheroids after injury

Abstract

Background Neuronal injury leads to rapid, programmed disintegration of axons distal to the site of lesion. Much like other forms of axon degeneration ( e.g. developmental pruning, toxic insult from neurodegenerative disorder), Wallerian degeneration associated with injury is preceded by spheroid formation along axons. The mechanisms by which injury leads to formation of spheroids remains elusive. Methods Here, using wild-type and mutant neonatal mouse primary sympathetic neurons, immunostaining and calcium imaging, we investigate the roles of players previously implicated in the progression of Wallerian degeneration in injury-induced spheroid formation. Results We find that intra-axonal calcium flux is accompanied by actin-Rho dependent growth of calcium rich axonal spheroids that eventually rupture, releasing material to the extracellular space prior to catastrophic axon degeneration. Importantly, after injury, Sarm1 -/- and DR6 -/- , but not Wld s (excess NAD + ) neurons, are capable of forming spheroids that eventually rupture, releasing their contents to the extracellular space. Supplementation of exogenous NAD + or expressing WLD s suppresses Rho-dependent spheroid formation and degeneration in response to injury. Conclusions Taken together, our findings place Rho-actin and NAD + upstream of spheroid formation and may suggest that other mediators of degeneration, such as DR6 and SARM1, mediate post-spheroid rupture events that lead to catastrophic axon disassembly.

What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?

“…41 NAD + suppresses this process, whereas SARM1 mediates postspheroid rupture events that lead to axon disassembly. 56 There are alterations of NAD + metabolism in induced pluripotent stem cell–derived dopaminergic neurons with PD-associated GBA (α-glucocerebrosidase) mutations 57 ; there are also higher levels of SARM1 in PD neurons with mutations in parkin . 58 However, blocking programmed axon death by SARM1 depletion does not protect against neurodegeneration in all PD models, 59 suggesting some are not SARM1-dependent or there is pathway redundancy.…”