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Morphological and Functional Evaluation of Axons and their Synapses during Axon Death in Drosophila melanogaster
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DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote

Daniel W Summers1,2,3, Erin Frey3, Lauren J Walker3

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

Molecular Neurobiology
|November 8, 2019
PubMed

Insights

Dual leucine zipper kinase (DLK) activation increases axon vulnerability in neurological disorders by reducing survival factors NMNAT2 and SCG10. This makes axons susceptible to injury and metabolic stress.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Axon degeneration is a key feature of neurological disorders.
  • Dual leucine zipper kinase (DLK) is a stress-activated MAP3K chronically activated in neurodegenerative diseases.
  • The role of DLK signaling in axon vulnerability is not well understood.

Purpose of the Study:

  • To investigate the impact of enhanced DLK signaling on axon vulnerability.
  • To identify cellular pathways mediating DLK-induced axon degeneration.

Main Methods:

  • Stimulation of DLK activity in axons.
  • Assessment of axon degeneration.
  • Measurement of NMNAT2 and SCG10 levels in axons.
  • Induction of mitochondrial dysfunction.

Main Results:

  • DLK activation predisposes axons to SARM1-dependent degeneration.
  • Activated DLK reduces axonal levels of NMNAT2 and SCG10.
  • Mitochondrial dysfunction exacerbates NMNAT2/SCG10 loss and causes spontaneous axon degeneration when combined with DLK activation.

Conclusions:

  • Enhanced DLK signaling compromises axon integrity by lowering survival factor abundance.
  • DLK activity increases susceptibility to axonal trauma and metabolic insults.
  • Targeting DLK signaling may offer therapeutic strategies for neurodegenerative diseases.
Keywords:
AxonDLKMitochondriaNMNAT2SARM1STMN2

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