Cell
Volume 160, Issues 1–2, 15 January 2015, Pages 161-176
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Article
Pathological Axonal Death through a MAPK Cascade that Triggers a Local Energy Deficit

https://doi.org/10.1016/j.cell.2014.11.053Get rights and content
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Highlights

  • A MAPK cascade is a central pathway underlying pathological axon degeneration

  • Sarm1 is required for activation of the MAPK cascade in this degenerative response

  • Sarm1-MAPK pathway triggers a local energy deficit in axons leading to degeneration

  • CytoNmnat1/Wlds and AKT converge on the MAPK cascade to regulate axon degeneration

Summary

Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wlds protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration.

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