Skip to main content
SpringerLink
Log in

DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration

Molecular Neurobiology Aims and scope Submit manuscript

Cite this article

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Gerdts J, Summers DW, Milbrandt J, DiAntonio A (2016) Axon self-destruction: new links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 89:449–460. https://doi.org/10.1016/j.neuron.2015.12.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. DiAntonio A (2019) Axon degeneration: mechanistic insights lead to therapeutic opportunities for the prevention and treatment of peripheral neuropathy. Pain 160(Suppl 1):S17–S22. https://doi.org/10.1097/j.pain.0000000000001528

    Article  CAS  PubMed  Google Scholar 

  3. Le Pichon CE, Meilandt WJ, Dominguez S et al (2017) Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease. Sci Transl Med 9:eaag0394. https://doi.org/10.1126/scitranslmed.aag0394

    Article  CAS  PubMed  Google Scholar 

  4. Asghari Adib E, Smithson LJ, Collins CA (2018) An axonal stress response pathway: degenerative and regenerative signaling by DLK. Curr Opin Neurobiol 53:110–119. https://doi.org/10.1016/j.conb2018.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  6. Watkins TA, Wang B, Huntwork-Rodriguez S et al (2013) DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc Natl Acad Sci 110:4039–4044. https://doi.org/10.1073/pnas.1211074110

    Article  Google Scholar 

  7. Shin JE, Ha H, Kim YK, Cho Y, DiAntonio A (2019) DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury. Neurobiol Dis 127:178–192. https://doi.org/10.1016/j.nbd.2019.02.001

    Article  CAS  PubMed  Google Scholar 

  8. Shin JE, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A (2012) Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74:1015–1022. https://doi.org/10.1016/j.neuron.2012.04.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hammarlund M, Nix P, Hauth L et al (2009) Axon regeneration requires a conserved MAP kinase pathway. Science (80- ) 323:802–806. https://doi.org/10.1126/science.1165527

    Article  CAS  Google Scholar 

  10. Yan D, Wu Z, Chisholm AD, Jin Y (2009) The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138:1005–1018. https://doi.org/10.1016/j.cell.2009.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xiong X, Wang X, Ewanek R, Bhat P, Diantonio A, Collins CA (2010) Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. J Cell Biol 191:211–223. https://doi.org/10.1083/jcb.201006039

    Article  CAS  PubMed  PubMed Central  Google 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

  13. Ghosh-Roy A, Wu Z, Goncharov A et al (2010) Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. J Neurosci. https://doi.org/10.1523/jneurosci.5464-09.2010

    Article  CAS  Google Scholar 

  14. Fernandes KA, Harder JM, John SW, Shrager P, Libby RT (2014) DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury. Neurobiol Dis 69:108–116. https://doi.org/10.1016/j.nbd.2014.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  Google Scholar 

  16. Ghosh AS, Wang B, Pozniak CD, Chen M, Watts RJ, Lewcock JW (2011) DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity. J Cell Biol 194:751–764. https://doi.org/10.1083/jcb.201103153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pozniak CD, Sengupta Ghosh A, Gogineni A et al (2013) Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration. J Exp Med 210:2553–2567. https://doi.org/10.1084/jem.20122832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA et al (2012) dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337:481–484. https://doi.org/10.1126/science.1223899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J (2013) Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci 33:13569–13580. https://doi.org/10.1523/JNEUROSCI.1197-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Essuman K, Summers DW, Sasaki Y et al (2017) The SARM1 Toll/Interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity that promotes pathological axonal degeneration. Neuron 93:1334–1343.e5. https://doi.org/10.1016/j.neuron.2017.02.022

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  PubMed  PubMed Central  Google Scholar 

  22. Summers DW, DiAntonio A, Milbrandt J (2014) Mitochondrial dysfunction induces sarm1-dependent cell death in sensory neurons. J Neurosci 34:9338–9350. https://doi.org/10.1523/JNEUROSCI.0877-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ziogas NK, Koliatsos VE (2018) Primary traumatic axonopathy in mice subjected to impact acceleration: a reappraisal of pathology and mechanisms with high-resolution anatomical methods. J Neurosci:2343–2317. https://doi.org/10.1523/JNEUROSCI.2343-17.2018

    Article  CAS  Google Scholar 

  24. Geisler S, Doan RA, Strickland A, Huang X, Milbrandt J, DiAntonio A (2016) Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 139:3092–3108. https://doi.org/10.1093/brain/aww251

    Article  PubMed  PubMed Central  Google Scholar 

  25. Turkiew E, Falconer D, Reed N, Höke A (2017) Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy. J Peripher Nerv Syst 22:162–171. https://doi.org/10.1111/jns.12219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C, Iadecola C, Nathan C et al (2007) MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med 204:2063–2074. https://doi.org/10.1084/jem.20070868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Godzik K, Coleman MP (2015) The axon-protective WLDS protein partially rescues mitochondrial respiration and glycolysis after axonal injury. J Mol Neurosci 55:865–871. https://doi.org/10.1007/s12031-014-0440-2

    Article  CAS  PubMed  Google Scholar 

  28. Gilley J, Orsomando G, Nascimento-Ferreira I, Coleman MP (2015) Absence of SARM1 rescues development and survival of NMNAT2-Deficient axons. Cell Rep 10:1975–1982. https://doi.org/10.1016/j.celrep.2015.02.060

    Article  CAS  Google 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

  30. Huppke P, Wegener E, Gilley J, Angeletti C, Kurth I, Drenth JPH, Stadelmann C, Barrantes-Freer A et al (2019) Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia. Exp Neurol 320:112958. https://doi.org/10.1016/j.expneurol.2019.112958

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google Scholar 

  33. Melamed Z, López-Erauskin J, Baughn MW et al (2019) Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci 22:180–190. https://doi.org/10.1038/s41593-018-0293-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shin JE, Miller BR, Babetto E, Cho Y, Sasaki Y, Qayum S, Russler EV, Cavalli V et al (2012) SCG10 is a JNK target in the axonal degeneration pathway. Proc Natl Acad Sci U S A 109:E3696–E3705. https://doi.org/10.1073/pnas.1216204109

    Article  PubMed  PubMed Central  Google 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

  36. Summers DW, Milbrandt J, DiAntonio A (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. Proc Natl Acad Sci 115:E8746–E8754. https://doi.org/10.1073/pnas.1806933115

    Article  CAS  PubMed  Google Scholar 

  37. Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A (2009) A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat Neurosci 12:387–389. https://doi.org/10.1038/nn.2290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, Greer PA, Tournier C et al (2015) Pathological axonal death through a Mapk cascade that triggers a local energy deficit. Cell 160:161–176. https://doi.org/10.1016/j.cell.2014.11.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J (2015) SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science 348:453–457. https://doi.org/10.1126/science.1258366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Milde S, Gilley J, Coleman MP (2013) Subcellular localization determines the stability and axon protective capacity of axon survival factor Nmnat2. PLoS Biol 11. https://doi.org/10.1371/journal.pbio.1001539

    Article  CAS  Google Scholar 

  42. Misgeld T, Schwarz TL (2017) Mitostasis in neurons: maintaining mitochondria in an extended cellular architecture. Neuron 96:651–666. https://doi.org/10.1016/j.neuron.2017.09.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306. https://doi.org/10.1038/81834

    Article  CAS  PubMed  Google Scholar 

  44. Green DR, Galluzzi L, Kroemer G (2014) Metabolic control of cell death. Science (80- ) 345:1250256–1250256. https://doi.org/10.1126/science.1250256

    Article  CAS  Google Scholar 

  45. Ali YO, Allen HM, Yu L, Li-Kroeger D, Bakhshizadehmahmoudi D, Hatcher A, McCabe C, Xu J et al (2016) NMNAT2:HSP90 complex mediates proteostasis in proteinopathies. PLoS Biol 14:e1002472. https://doi.org/10.1371/journal.pbio.1002472

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  Google Scholar 

  47. Xiong X, Collins CA (2012) A conditioning lesion protects axons from degeneration via the Wallenda/DLK MAP kinase signaling cascade. J Neurosci 32:610–615. https://doi.org/10.1523/JNEUROSCI.3586-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Valakh V, Frey E, Babetto E, Walker LJ, DiAntonio A (2015) Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. Neurobiol Dis 77:13–25. https://doi.org/10.1016/j.nbd.2015.02.014

    Article  CAS  PubMed  PubMed Central  Google 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

  50. Huang YWA, Zhou B, Wernig M, Südhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168:427–441.e21. https://doi.org/10.1016/j.cell.2016.12.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

  52. Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, Dahlman JE, Parnas O et al (2014) CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell 159:440–455. https://doi.org/10.1016/j.cell.2014.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gerdts J, Sasaki Y, Vohra B, Marasa J, Milbrandt J (2011) Image-based screening identifies novel roles for I{kappa}B kinase and glycogen synthase kinase 3 in axonal degeneration. J Biol Chem 286:28011–28018. https://doi.org/10.1074/jbc.M111.250472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the members of the DiAntonio and Milbrandt labs for their constructive feedback in the generation of this manuscript.

Funding

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).

Author information

Authors and Affiliations

  1. Department of Biology, University of Iowa, Iowa City, IA, 52242, USA

    Daniel W. Summers

  2. Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, 52242, USA

    Daniel W. Summers

  3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Daniel W. Summers, Erin Frey, Lauren J. Walker & Aaron DiAntonio

  4. Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Jeffrey Milbrandt

  5. Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Jeffrey Milbrandt & Aaron DiAntonio

Authors
  1. Daniel W. Summers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erin Frey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lauren J. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey Milbrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aaron DiAntonio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jeffrey Milbrandt or Aaron DiAntonio.

Ethics declarations

Competing Interests

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 2825 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Summers, D.W., Frey, E., Walker, L.J. et al. DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration. Mol Neurobiol 57, 1146–1158 (2020). https://doi.org/10.1007/s12035-019-01796-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-01796-2

Keywords

search

Navigation