| First Author | Wan Y | Year | 2023 |
| Journal | J Cell Biol | Volume | 222 |
| Issue | 2 | PubMed ID | 36482480 |
| Mgi Jnum | J:336792 | Mgi Id | MGI:7425455 |
| Doi | 10.1083/jcb.202208108 | Citation | Wan Y, et al. (2023) KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway. J Cell Biol 222(2) |
| abstractText | 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. |
