DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration
Axon degeneration is a prominent component of many neurological disorders. Identifying cellular pathways that contribute to axon vulnerability may identify new therapeutic strategies for maintenance of neural circuits. Dual leucine zipper kinase (DLK) is an axonal stress response MAP3K that is chronically activated in several neurodegenerative diseases. Activated DLK transmits an axon injury signal to the neuronal cell body to provoke transcriptional adaptations. However, the consequence of enhanced DLK signaling to axon vulnerability is unknown. We find that stimulating DLK activity predisposes axons to SARM1-dependent degeneration. Activating DLK reduces levels of the axon survival factors NMNAT2 and SCG10, accelerating their loss from severed axons. Moreover, mitochondrial dysfunction independently decreases the levels of NMNAT2 and SCG10 in axons, and in conjunction with DLK activation, leads to a dramatic loss of axonal NMNAT2 and SCG10 and evokes spontaneous axon degeneration. Hence, enhanced DLK activity reduces axon survival factor abundance and renders axons more susceptible to trauma and metabolic insult.
KeywordsDLK NMNAT2 Axon SARM1 Mitochondria STMN2
We thank the members of the DiAntonio and Milbrandt labs for their constructive feedback in the generation of this manuscript.
D.W.S is supported by a Development Grant from the Muscular Dystrophy Association (MDA344513). This work was also supported by funds from the National Institutes of Health (RO1-NS65053 to A.D., RF1-AG013730 to J.M, RO1-NS087632 to J.M and A.D., and RO1-CA219866 to A.D. and J.M).
Compliance with Ethical Standards
A.D and J.M are co-founders of Disarm Therapeutics and members of the Scientific Advisory Board. The authors have no additional competing financial interests.
- 5.Farley MM, Watkins TA (2018) Intrinsic neuronal stress response pathways in injury and disease. Annu Rev Pathol Mech Dis. https://doi.org/10.1146/annurev-pathol-012414-040354 CrossRefGoogle Scholar
- 12.Hao Y, Frey E, Yoon C et al (2016) An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK. Elife:5. https://doi.org/10.7554/eLife.14048
- 15.Welsbie DS, Yang Z, Ge Y, Mitchell KL, Zhou X, Martin SE, Berlinicke CA, Hackler L Jr et al (2013) Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death. Proc Natl Acad Sci 110:4045–4050. https://doi.org/10.1073/pnas.1211284110 CrossRefPubMedGoogle Scholar
- 21.Henninger N, Bouley J, Sikoglu EM, An J, Moore CM, King JA, Bowser R, Freeman MR et al (2016) Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1. Brain 139:1094–1105. https://doi.org/10.1093/brain/aww001 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Sasaki Y, Nakagawa T, Mao X et al (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD(+) depletionx. J Neurosci:2343–2317. https://doi.org/10.7554/eLife.19749
- 31.Lukacs M, Gilley J, Zhu Y, Orsomando G, Angeletti C, Liu J, Yang X, Park J et al (2019) Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence. Exp Neurol 320:112961. https://doi.org/10.1016/j.expneurol.2019.112961 CrossRefPubMedGoogle Scholar
- 32.Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA, Burberry A, Steinbaugh MJ et al (2019) ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci 22:167–179. https://doi.org/10.1038/s41593-018-0300-4 CrossRefPubMedGoogle Scholar
- 35.Walker LJ, Summers DW, Sasaki Y et al (2017) MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. Elife 6. https://doi.org/10.7554/eLife.22540
- 39.Welsbie DS, Mitchell KL, Jaskula-Ranga V, Sluch VM, Yang Z, Kim J, Buehler E, Patel A et al (2017) Enhanced functional genomic screening identifies novel mediators of dual leucine zipper kinase-dependent injury signaling in neurons. Neuron 94:1142–1154. https://doi.org/10.1016/j.neuron.2017.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
- 46.Ljungberg MC, Ali YO, Zhu J, Wu CS, Oka K, Zhai RG, Lu HC (2012) CREB-activity and NMNAT2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Hum Mol Genet 21:251–267. https://doi.org/10.1093/hmg/ddr492 CrossRefPubMedGoogle Scholar
- 49.Li J, Zhang YV, Adib EA et al (2017) Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104. Elife 6. https://doi.org/10.7554/eLife.24271
- 51.Ali YO, Bradley G, Lu HC (2017) Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Sci Rep 7. https://doi.org/10.1038/srep43846