title: SCG10 is a JNK target in the axonal degeneration pathway.
abstract: Axons actively self-destruct following genetic, mechanical, metabolic, and toxic insults, but the mechanism of axonal degeneration is poorly understood. The JNK pathway promotes axonal degeneration shortly after axonal injury, hours before irreversible axon fragmentation ensues. Inhibition of JNK activity during this period delays axonal degeneration, but critical JNK substrates that facilitate axon degeneration are unknown. Here we show that superior cervical ganglion 10 (SCG10), an axonal JNK substrate, is lost rapidly from mouse dorsal root ganglion axons following axotomy. SCG10 loss precedes axon fragmentation and occurs selectively in the axon segments distal to transection that are destined to degenerate. Rapid SCG10 loss after injury requires JNK activity. The JNK phosphorylation sites on SCG10 are required for its rapid degradation, suggesting that direct JNK phosphorylation targets SCG10 for degradation. We present a mechanism for the selective loss of SCG10 distal to the injury site. In healthy axons, SCG10 undergoes rapid JNK-dependent degradation and is replenished by fast axonal transport. Injury blocks axonal transport and the delivery of SCG10, leading to the selective loss of the labile SCG10 distal to the injury site. SCG10 loss is functionally important: Knocking down SCG10 accelerates axon fragmentation, whereas experimentally maintaining SCG10 after injury promotes mitochondrial movement and delays axonal degeneration. Taken together, these data support the model that SCG10 is an axonal-maintenance factor whose loss is permissive for execution of the injury-induced axonal degeneration program.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Shin
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Miller
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Babetto
authors.forename: Yongcheol
authors.initials: Y
authors.lastname: Cho
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Shehzad
authors.initials: S
authors.lastname: Qayum
authors.forename: Emilie V
authors.initials: EV
authors.lastname: Russler
authors.forename: Valeria
authors.initials: V
authors.lastname: Cavalli
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: Aaron
authors.initials: A
authors.lastname: DiAntonio
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D050777:Stathmin
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050777:Stathmin; C512849:Stmn2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex