2. Academic Validation
  3. DLK-dependent axonal mitochondrial fission drives degeneration after axotomy

DLK-dependent axonal mitochondrial fission drives degeneration after axotomy

  • Nat Commun. 2024 Dec 30;15(1):10806. doi: 10.1038/s41467-024-54982-9.
Jorge Gómez-Deza 1,  Matthew Nebiyou 1,  Mor R Alkaslasi 1,  Francisco M Nadal-Nicolás 2,  Preethi Somasundaram 3,  Anastasia L Slavutsky 1,  Wei Li 2,  Michael E Ward 4,  Trent A Watkins 3 5,  Claire E Le Pichon 6
Affiliations

Affiliations

  • 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • 2 National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
  • 4 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 5 Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
  • 6 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. [email protected].
PMID: 39737939 DOI: 10.1038/s41467-024-54982-9
Abstract

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of Dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive Apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention.

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