SCG10 is a JNK target in the axonal degeneration pathway

Jung Eun Shin, Bradley R. Miller, Elisabetta Babetto, Yongcheol Cho, Yo Sasaki, Shehzad Qayum, Emilie V. Russler, Valeria Cavalli, Jeffrey Milbrandt, Aaron DiAntonio

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E3696-E3705
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number52
DOIs
Publication statusPublished - 2012 Dec 26

ASJC Scopus subject areas

  • General

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