Yang, JingWu, ZhuhaoRenier, NicolasSimon, David J.Uryu, KunihiroPark, David S.Greer, Peter A.Tournier, CathyDavis, Roger J.Tessier-Lavigne, Marc2022-08-232022-08-232015-01-152016-02-19Cell. 2015 Jan 15;160(1-2):161-76. doi: 10.1016/j.cell.2014.11.053. <a href="http://dx.doi.org/10.1016/j.cell.2014.11.053">Link to article on publisher's site</a>0092-8674 (Linking)10.1016/j.cell.2014.11.05325594179https://hdl.handle.net/20.500.14038/28283Axonal 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.en-USAdenosine TriphosphateAnimalsArmadillo Domain ProteinsAxonsCell DeathCytoskeletal ProteinsMAP Kinase Kinase 4*MAP Kinase Signaling SystemMiceNeurodegenerative DiseasesProto-Oncogene Proteins c-aktRetinal Ganglion CellsBiochemistryCell BiologyCellular and Molecular PhysiologyMolecular BiologyJournal Articlehttps://escholarship.umassmed.edu/davis/138179692davis/13