DLK-dependent mitochondrial fission drives axon degeneration and neuronal cell death.
bioRxiv
; 2023 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-36778383
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 developed a robust human iPSCbased model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers a wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrated that mitochondrial fission and resultant cell death is entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) by dual leucine zipper kinase (DLK). Importantly, we show that CRISPR mediated Drp1 depletion protected mouse retinal ganglion neurons from mitochondrial fission and degeneration after optic nerve crush. Our results provide a powerful platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and new focus for therapeutic intervention.
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01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article