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Neurons dispose of hyperactive kinesin into glial cells for clearance.
- Source :
- EMBO Journal; Jul2024, Vol. 43 Issue 13, p2606-2635, 30p
- Publication Year :
- 2024
-
Abstract
- Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins. Synopsis: Hyperactivation of kinesins has been linked to neurodegenerative conditions. This study shows that a hyperactive version of OSM-3, a member of kinesin-2 superfamily that drives anterograde intraflagellar transport in C. elegans, is expelled from neurons for degradation in glial cells. Hyperactive OSM-3CA kinesin is absent from cilia and forms dynamic puncta within the neurites of sensory neurons. OSM-3CA puncta are ejected from sensory neurons and engulfed by neighboring cephalic sheath glia cells in a manner dependent of the phagocytic receptor CED-1. Mutations that reduce OSM-3CA activity or increase its microtubule binding protect OSM-3CA and restore normal cilia. ALS-linked hyperactive kinesin-1 is also expelled from neurons when ectopically expressed in C. elegans. Phagocytic receptor CED-1 enables glial uptake and subsequent degradation of hyperactive kinesins in C. elegans. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02614189
- Volume :
- 43
- Issue :
- 13
- Database :
- Complementary Index
- Journal :
- EMBO Journal
- Publication Type :
- Academic Journal
- Accession number :
- 178210753
- Full Text :
- https://doi.org/10.1038/s44318-024-00118-0