Sodium and Potassium Currents Influence Wallerian Degeneration of InjuredDrosophilaAxons

Abstract

Axons degenerate after injury and in neuropathies and disease via a self-destruction program whose mechanism is poorly understood. Axons that have lost connection to their cell bodies have altered electrical and synaptic activities, but whether such changes play a role in the axonal degeneration process is not clear. We have used a Drosophila model to study the Wallerian degeneration of motoneuron axons and their neuromuscular junction synapses. We found that degeneration of the distal nerve stump after a nerve crush is greatly delayed when there is increased potassium channel activity (by overexpression of two different potassium channels, Kir2.1 and dORK⌬-C) or decreased voltage-gated sodium channel activity (using mutations in the para sodium channel). Conversely, degeneration is accelerated when potassium channel activity is decreased (by expressing a dominant-negative mutation of Shaker). Despite the effect of altering voltage-gated sodium and potassium channel activity, recordings made after nerve crush demonstrated that the distal stump does not fire action potentials. Rather, a variety of lines of evidence suggest that the sodium and potassium channels manifest their effects upon degeneration through changes in the resting membrane potential, which in turn regulates the level of intracellular free calcium within the isolated distal axon.

A Surviving Intact Branch Stabilizes Remaining Axon Architecture after Injury as Revealed by In Vivo Imaging in the Mouse Spinal Cord

“…Alternatively, synaptic activities in the distal segment may accelerate acute degeneration. However, a recent study in Drosophila showed that following axotomy the distal stump does not fire action potentials (Mishra et al, 2013), arguing against a major role for nerve excitability or synaptic activity in distal degeneration.…”

Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism

“…Identification of these key nodes in the program provides a framework for understanding the mechanism of additional genes and drugs that modulate axon degeneration. Multiple investigators are identifying factors that can affect the degeneration program, and at least a subset is likely to impinge on the NMNAT2/SARM1/MAPK program (Barrientos et al, 2011; Bhattacharya et al, 2012; Brace et al, 2014; Mishra et al, 2013; Wakatsuki et al, 2011). Two exciting recent examples are the identification of the PHR ubiquitin ligase as an important regulator of NMNAT2 levels, and of the kinase AKT as a negative regulator of MKK4.…”

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

“…Drosophila is a powerful model for investigating fundamental aspects of neurodegeneration and glial responses to neural damage (Ayaz et al, 2008; Cantera and Barrio, 2015; Etchegaray et al, 2016; Fang and Bonini, 2012; Freeman et al, 2003; Kato et al, 2011; Lee and Sun, 2015; Logan and Freeman, 2007; Liu et al, 2015; Mishra et al, 2013; Rooney and Freeman, 2014; Ugur et al, 2016). Axotomy in adult flies elicits glial reactions that share many cellular hallmarks with mammalian glia responding to neurodegeneration, including altered morphology and increased phagocytic function (Kurant 2011; Logan and Freeman, 2007).…”