Programmed axon degeneration: from mouse to mechanism to medicine

Abstract

Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (WldS) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of ‘druggable’ enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.

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Fig. 1: Activation of Wallerian degeneration in injury and disease.
Fig. 2: Wallerian degeneration timeline.
Fig. 3: A working model of the Wallerian degeneration pathway.
Fig. 4: Activation of SARM1 by NMN.
Fig. 5: An axon vulnerability spectrum in humans and mice.

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Acknowledgements

The authors thank members of the Coleman group for constructive feedback.

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The authors contributed equally to all aspects of the article.

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Correspondence to Michael P. Coleman or Ahmet Höke.

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M.P.C. has an academic collaboration with AstraZeneca and is a consultant for Proneurotech. A.H. serves on the scientific advisory board of Disarm Therapeutics.

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Glossary

Wallerian degeneration slow (Wld S) mice

A mutant strain of mouse showing a tenfold delay in the onset of Wallerian degeneration after axotomy as well as axon protection in many disease models.

Axonal transport

The ATP-dependent, bidirectional trafficking of axonal proteins, organelles, mRNAs and other cargoes delivering axonal constituents to where they are required, often over large distances.

Toll-like receptor

A family of receptors on plasma and endosomal membranes that detect molecular patterns associated with infection or cell damage, activating signalling pathways leading to inflammation or cell death.

Calcium mobilization

The release of calcium from intracellular stores such as endoplasmic reticulum and mitochondria, potentially activating calcium-activated proteases, under the control of second messenger molecules (many of which are NAD metabolites).

Local translation

The synthesis of proteins directly within axons using mRNAs delivered by axonal transport.

Stathmin 2

A protein that, like NMNAT2, is palmitoylated, has a short half-life and negatively regulates Wallerian degeneration. Its loss is insufficient to activate Wallerian degeneration but accelerates it after injury and its overexpression delays degeneration. The same protein is depleted in many induced pluripotent stem cell-derived motor neurons from sporadic amyotrophic lateral sclerosis patients.

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Coleman, M.P., Höke, A. Programmed axon degeneration: from mouse to mechanism to medicine. Nat Rev Neurosci 21, 183–196 (2020). https://doi.org/10.1038/s41583-020-0269-3

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