Pathological axonal death through a MAPK cascade that triggers a local energy deficit

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Program in Molecular Medicine

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Adenosine Triphosphate; Animals; Armadillo Domain Proteins; Axons; Cell Death; Cytoskeletal Proteins; MAP Kinase Kinase 4; *MAP Kinase Signaling System; Mice; Neurodegenerative Diseases; Proto-Oncogene Proteins c-akt; Retinal Ganglion Cells


Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology


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.

DOI of Published Version



Cell. 2015 Jan 15;160(1-2):161-76. doi: 10.1016/j.cell.2014.11.053. Link to article on publisher's site

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