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Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8746-E8754. doi: 10.1073/pnas.1806933115. Epub 2018 Aug 27.

Palmitoylation enables MAPK-dependent proteostasis of axon survival factors.

Author information

1
Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110.
2
Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110.
3
Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110; jmilbrandt@wustl.edu diantonio@wustl.edu.
4
Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, St. Louis, MO 63110.
5
Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110; jmilbrandt@wustl.edu diantonio@wustl.edu.

Abstract

Axon degeneration is a prominent event in many neurodegenerative disorders. Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by constant delivery of the axon survival factor NMNAT2. Elevating NMNAT2 is neuroprotective, while loss of NMNAT2 evokes SARM1-dependent axon degeneration. As a gatekeeper of axon survival, NMNAT2 abundance is an important regulatory node in neuronal health, highlighting the need to understand the mechanisms behind NMNAT2 protein homeostasis. We demonstrate that pharmacological inhibition of the MAP3Ks dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) elevates NMNAT2 abundance and strongly protects axons from injury-induced degeneration. We discover that MAPK signaling selectively promotes degradation of palmitoylated NMNAT2, as well as palmitoylated SCG10. Conversely, nonpalmitoylated NMNAT2 is degraded by the Phr1/Skp1a/Fbxo45 ligase complex. Combined inactivation of both pathways leads to synergistic accumulation of NMNAT2 in axons and dramatically enhanced protection against pathological axon degeneration. Hence, the subcellular localization of distinct pools of NMNAT2 enables differential regulation of NMNAT2 abundance to control axon survival.

KEYWORDS:

DLK; NMNAT2; SARM1; SCG10; axon

PMID:
30150401
PMCID:
PMC6140512
DOI:
10.1073/pnas.1806933115
[Indexed for MEDLINE]
Free PMC Article

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