Pathological axonal death through a MAPK cascade that triggers a local energy deficit
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Authors
Yang, JingWu, Zhuhao
Renier, Nicolas
Simon, David J.
Uryu, Kunihiro
Park, David S.
Greer, Peter A.
Tournier, Cathy
Davis, Roger J.
Tessier-Lavigne, Marc
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2015-01-15Keywords
Adenosine TriphosphateAnimals
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
Metadata
Show full item recordAbstract
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.Source
Cell. 2015 Jan 15;160(1-2):161-76. doi: 10.1016/j.cell.2014.11.053. Link to article on publisher's siteDOI
10.1016/j.cell.2014.11.053Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28283PubMed ID
25594179Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.cell.2014.11.053