title: Pathological axonal death through a MAPK cascade that triggers a local energy deficit.
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.
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Zhuhao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renier
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Simon
authors.affiliation: Electron Microscopy Resource Center, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.affiliation: University of Ottawa Brain and Mind Research Institute, University of Ottawa, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.affiliation: Queen's University Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.affiliation: University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Tournier
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA. Electronic address: marctl@rockefeller.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000473:pathology*; D016923:Cell Death; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; C543961:SARM1 protein, mouse; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4