Publication Date
12-30-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-54982-9
PMID
39737939
PMCID
PMC11686342
PubMedCentral® Posted Date
12-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Mitochondrial Dynamics, Animals, Humans, Axotomy, Axons, Mice, Dynamins, Retinal Ganglion Cells, Induced Pluripotent Stem Cells, Apoptosis, Phosphorylation, MAP Kinase Kinase Kinases, Nerve Degeneration, Optic Nerve Injuries, Nerve Crush, Neurodegeneration, Cell death in the nervous system, Mechanisms of disease
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.