MAPK cascade promotes early axonal degeneration in response to injury


Axons connect neurons are essential for neural circuits formation. The death of axon is associated to many neurodegenerative disorders including traumatic injury. By using traumatic injury as a model, Yang et al. demonstrated a critical role of mitogen-activated protein kinase (MAPK) cascade in early axonal degeneration in response to injury. The article was published on Cell, recently.


Previous studies showed the suppression of Sarm1, a Toll receptor adaptor protein, significantly delays axonal degeneration after injury. Researchers found Sarm1, in response to early axonal injury, is required for the activation of MAPK cascade, which leads to disruption of local energy homeostasis, ATP depletion, activation of calpains, at last, breakdown of axonal structures. They found a central regulatory factor of MAPK pathway, MAPK kinase 4 (MKK4), limits activation of downstream molecule c-Jun N-terminal kinases (JNKs) to modulate early injury response. Furthermore, a cytosolic version of nocotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which is related to NAD+ synthesis, was found to inhibit the MAPK pathway activation. In conclusion, the findings reveal a novel MAPK pathway-centered regulatory mechanism in promoting pathological axon degeneration through inducing local energy deficit.


Cell. 2015 Jan 15;160(1-2):161-76.

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