Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons

Abstract

We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related WldS protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.

Abstract

The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletion of Nmnat2 is sufficient to induce Wallerian-like degeneration of uninjured axons which endogenous Nmnat1 and Nmnat3 cannot prevent. Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins. Nmnat2 turnover is equally rapid in injured Wld ^S neurites, despite delayed neurite degeneration, showing it is not a consequence of degeneration and also that Wld ^S does not stabilize Nmnat2. Depletion of Nmnat2 below a threshold level is necessary for axon degeneration since exogenous Nmnat2 can protect injured neurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2 turnover and neurite degeneration. We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related Wld ^S protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.

Author Summary

In a normally functioning neuron, the cell body supplies the axon with materials needed to keep it healthy. This complex logistical activity breaks down completely after injury and often becomes compromised in neurodegenerative diseases, leading to degeneration of the isolated axon. Whilst there are probably many important cargoes delivered from the cell body that isolated axons cannot exist without indefinitely, proteins that are short-lived will be depleted first, so loss of these proteins is likely to act as a trigger for degeneration. Using clues from a mutant mouse whose axons are protected from such degeneration, we have identified delivery of Nmnat2, a protein with an important enzyme activity, as a limiting factor in axon survival. Importantly, Nmnat2 is very labile and its levels decline rapidly in injured axons before they start to degenerate. Even uninjured axons degenerate in a similar way without it. These properties are consistent with loss of Nmnat2 being a natural stimulus for axon degeneration, and it might therefore be a suitable target for therapeutic intervention.