Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Academic Article uri icon

Overview

abstract

  • 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/Wld(s) 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.

publication date

  • January 15, 2015

Research

keywords

  • Axons
  • MAP Kinase Signaling System

Identity

PubMed Central ID

  • PMC4306654

Scopus Document Identifier

  • 84920995116

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2014.11.053

PubMed ID

  • 25594179

Additional Document Info

volume

  • 160

issue

  • 1-2