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KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway.

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.

SUBMITTER: Wan Y

PROVIDER: S-EPMC9735414 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway.

Wan Yuansong Y Morikawa Momo M Morikawa Manatsu M Iwata Suguru S Naseer Muhammad Imran MI Ahmed Chaudhary Adeel Gulzar AG Tanaka Yosuke Y Hirokawa Nobutaka N

The Journal of cell biology 20221208 2

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. Be ...[more]

PMID: 36482480

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Project description:Epilepsy is one of the most prevalent and drug-refractory neurological disorders. Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and investigate its in epileptogenesis in in vivo and in vitro models through behavioral, electrophysiological, and pathological studies. We used kainic acid- and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons as experimental epileptic models in this study. We first found increased ZDHHC8 expression in the brains of temporal lobe epilepsy (TLE) patients, similar to that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is correlated with human epilepsy. In the in vitro seizure models, knocking down ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and epileptiform-like discharges, while ZDHHC8 overexpression had the opposite effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we observed that ZDHHC8 had a significant modulatory effect on 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further affecting the inward rectification of AMPA currents in acute hippocampal slices in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal surface in the hippocampus, as shown by immunoprecipitation and Western blotting. These results suggest that ZDHHC8 may promote the generation and propagation of seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic effects in drug-resistant epilepsy. Our study provides evidence that may facilitate the development of an alternative approach for the treatment of epilepsy by modulating AMPA/GluA1-mediated neurotransmission.

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KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway.

Publications

KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway.

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