[PDF][PDF] Pathological axonal death through a MAPK cascade that triggers a local energy deficit
Cell, 2015•cell.com
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 …
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 …
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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