Axon degeneration: where the Wlds things are

Abstract

Expression of the Wld(s) protein significantly delays axon degeneration in injuries and diseases, but the mechanism for this protection is unknown. Two recent reports present evidence that axonal mitochondria are required for Wld(S)-mediated axon protection.

Figure 1. A model of mitochondria-dependent axon protection

The Drosophila protein dNmnat is necessary and sufficient for axonal survival, as RNAi-mediated knockdown of endogenous dNmnat induces spontaneous axon degeneration and depletion of mitochondria in the axon (top left), while upregulation of dNmnat delays axon degeneration from axotomy and rescues the depletion of axonal mitochondria (top right). Blocking mitochondrial entry into the axon by knocking down Milton, a linker protein required for anterograde mitochondrial transport, leads to spontaneous axon degeneration (bottom left). This degeneration cannot be rescued even with upregulation of dNmnat (bottom right), indicating that axonal mitochondria are required for dNmnat-mediated maintenance of normal axon survival and axon protection following nerve injuries.

Figure 2. Wld^S activity in mitochondrial dynamics and function

(A) In injured wild-type (WT) axons, an influx of extracellular Ca²⁺ exceeds the threshold of mitochondrial Ca²⁺ buffering and leads to a local, transient increase of Ca²⁺ in the axon. Ca²⁺ binding to the Milton–Miro protein complex leads to undocking of mitochondria from the kinesin-dependent anterograde transport machinery, thereby decreasing mitochondrial movement. (B) In injured Wld^S axons, increased Ca²⁺ buffering by mitochondria decreases available free Ca²⁺ to bind to the Milton–Miro complex, thus maintaining the attachment of mitochondria to the anterograde transport machinery and preserving motility of mitochondria in the axon.