Journal article
Palmitoylation enables MAPK-dependent proteostasis of axon survival factors
Proceedings of the National Academy of Sciences - PNAS, Vol.115(37), pp.E8746-E8754
PNAS Plus
09/11/2018
DOI: 10.1073/pnas.1806933115
PMCID: PMC6140512
PMID: 30150401
Abstract
Neurons extend long structures called axons that are highly susceptible to damage and undergo degeneration in many neurological disorders. One strategy for treating these diseases is by elevating the abundance of axon survival factors that suppress axon death. Herein, we describe a protein homeostasis network that regulates axon degeneration by tuning the local levels of axon survival factors. In particular, we find that small-molecule inhibitors targeting a MAPK stress pathway protect axons from pathological degeneration by elevating the local abundance of axon survival factors NMNAT2 and SCG10. Furthermore, we discover that intracellular location imparts sensitivity to distinct protein homeostasis networks. Inactivating multiple nodes in this protein homeostasis network confers maximal therapeutic potential in diseases of axon degeneration.
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.
Details
- Title: Subtitle
- Palmitoylation enables MAPK-dependent proteostasis of axon survival factors
- Creators
- Daniel W Summers - Department of Developmental BiologyJeffrey Milbrandt - Department of GeneticsAaron DiAntonio - Department of Developmental Biology
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.115(37), pp.E8746-E8754
- Series
- PNAS Plus
- DOI
- 10.1073/pnas.1806933115
- PMID
- 30150401
- PMCID
- PMC6140512
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- AG013730 / HHS | National Institutes of Health (NIH) 344513 / Muscular Dystrophy Association (MDA) NS087632 / HHS | National Institutes of Health (NIH) 349925 / Muscular Dystrophy Association (MDA) CA219866 / HHS | National Institutes of Health (NIH) NS65053 / HHS | National Institutes of Health (NIH)
- Language
- English
- Date published
- 09/11/2018
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984070885102771
Metrics
17 Record Views