MEK inhibitor U0126 reverses protection of axons from Wallerian degeneration independently of MEK-ERK signaling.

Abstract

Wallerian degeneration is delayed when sufficient levels of proteins with NMNAT activity are maintained within axons after injury. This has been proposed to form the basis of 'slow Wallerian degeneration' (Wld (S)), a neuroprotective phenotype conferred by an aberrant fusion protein, Wld(S). Proteasome inhibition also delays Wallerian degeneration, although much less robustly, with stabilization of NMNAT2 likely to play a key role in this mechanism. The pan-MEK inhibitor U0126 has previously been shown to reverse the axon-protective effects of proteasome inhibition, suggesting that MEK-ERK signaling plays a role in delayed Wallerian degeneration, in addition to its established role in promoting neuronal survival. Here we show that whilst U0126 can also reverse Wld(S)-mediated axon protection, more specific inhibitors of MEK1/2 and MEK5, PD184352 and BIX02189, have no significant effect on the delay to Wallerian degeneration in either situation, whether used alone or in combination. This suggests that an off-target effect of U0126 is responsible for reversion of the axon protective effects of Wld(S) expression or proteasome inhibition, rather than inhibition of MEK1/2-ERK1/2 or MEK5-ERK5 signaling. Importantly, this off-target effect does not appear to result in alterations in the stabilities of either Wld(S) or NMNAT2.

• Authors: Catherine Evans, Simon J Cook, Michael P Coleman, Jonathan Gilley
• Journal: PloS one (PLoS One) Vol. 8 Issue 10 Pg. e76505 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24124570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butadienes
• Nitriles
• Protein Kinase Inhibitors
• U 0126
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP Kinase Kinase 5
• NMNAT2 protein, human
• Nicotinamide-Nucleotide Adenylyltransferase

Topics

• Animals
• Axons (drug effects, metabolism)
• Butadienes (pharmacology)
• Cell Line
• Enzyme Stability (drug effects)
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• MAP Kinase Kinase 5 (antagonists & inhibitors)
• MAP Kinase Signaling System (drug effects)
• Nicotinamide-Nucleotide Adenylyltransferase (metabolism)
• Nitriles (pharmacology)
• Phenotype
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Superior Cervical Ganglion (drug effects, metabolism)
• Wallerian Degeneration (drug therapy, metabolism)