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KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway.
- Source :
-
The Journal of cell biology [J Cell Biol] 2023 Feb 06; Vol. 222 (2). Date of Electronic Publication: 2022 Dec 08. - Publication Year :
- 2023
-
Abstract
- Epilepsy is a common neurological disease worldwide, and one of its causes is genetic abnormalities. Here, we identified a point mutation in KIF4A, a member of kinesin superfamily molecular motors, in patients with neurological disorders such as epilepsy, developmental delay, and intellectual disability. KIF4 is involved in the poly (ADP-ribose) polymerase (PARP) signaling pathway, and the mutation (R728Q) strengthened its affinity with PARP1 through elongation of the KIF4 coiled-coil domain. Behavioral tests showed that KIF4-mutant mice exhibited mild developmental delay with lower seizure threshold. Further experiments revealed that the KIF4 mutation caused aberrant morphology in dendrites and spines of hippocampal pyramidal neurons through PARP1-TrkB-KCC2 pathway. Furthermore, supplementing NAD, which activates PARP1, could modulate the TrkB-KCC2 pathway and rescue the seizure susceptibility phenotype of the mutant mice. Therefore, these findings indicate that KIF4 is engaged in a fundamental mechanism regulating seizure susceptibility and could be a potential target for epilepsy treatment.<br /> (© 2022 Wan et al.)
- Subjects :
- Mice
Animals
Signal Transduction
Kinesins genetics
Seizures genetics
Epilepsy
Subjects
Details
- Language :
- English
- ISSN :
- 1540-8140
- Volume :
- 222
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 36482480
- Full Text :
- https://doi.org/10.1083/jcb.202208108