Abstract
Author SummaryIn 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.
Highlights
The endogenous molecular trigger for Wallerian degeneration remains unknown
Our main hypothesis predicts that blocking synthesis of one or more putative axon survival factors should trigger Wallerian-like degeneration without injury, similar to that induced by blocking axonal transport [27,28]
Transport We found that an Nmnat2–enhanced green fluorescent protein fusion protein localizes to superior cervical ganglion * E-mail (SCG) neurites in highly defined particles shortly after being expressed (Video S1 and Figure 7D)
Summary
The endogenous molecular trigger for Wallerian degeneration remains unknown. Since transport is bi-directional, degeneration could be triggered by failed anterograde delivery of essential survival factors or by failed removal of harmful substances by retrograde transport. Defective anterograde transport seems more directly associated with axon loss than dysfunctional retrograde transport [9,10,11,12,13]. Extending an old model [14], we propose a ‘‘survival factor delivery hypothesis’’ of axon degeneration. We suggest that axon integrity requires continuous anterograde delivery of one or more labile, cell body–synthesized survival factors. Once supply is disrupted, following injury or other insult, levels of the limiting survival factor(s) will drop below a critical threshold due to natural turnover, activating an intrinsic axon degeneration program
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