Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associatedSCN2A-L1342P mutation.

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 45(3), P. e2027232024 - e2027232024

Published: Nov. 18, 2024

Neuronal hyperexcitability is a hallmark of epilepsy. It has been recently shown in rodent models seizures that microglia, the brain's resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interact with neurons regulate mediated by an epilepsy-causing genetic mutation found patients unknown. The SCN2A gene responsible for encoding voltage-gated sodium channel Nav1.2, one leading contributors monogenic epilepsies. Previously, we demonstrated recurring Nav1.2-L1342P leads male donor (KOLF2.1) human-induced pluripotent stem cell (hiPSC)-derived cortical neuron model. Microglia originate from different lineage (yolk sac) are not naturally present hiPSC-derived cultures. To study carrying disease-causing influence excitability, established coculture model comprising microglia. We display increased branch length enhanced process-specific calcium signal when cocultured neurons. Moreover, presence significantly lowered repetitive action potential firing current density channels mutation. Additionally, showed coculturing led reduction expression within axon initial segment Furthermore, release higher amount glutamate compared control Our work thus reveals critical role iPSC-derived sensing dampening

Language: Английский

Polo-like kinase 2 promotes microglial activation via regulation of the HSP90α/IKKβ pathway

Cell Reports, Journal Year: 2024, Volume and Issue: 43(10), P. 114827 - 114827

Published: Oct. 1, 2024

Highlights•LPS rapidly induces PLK2 expression in microglial cells•Inhibition of suppresses LPS-induced activation via NF-κB signaling•PLK2 activates signaling through phosphorylating HSP90α•Knockout microglia ameliorated neuroinflammation and dopaminergic neuron lossSummaryPolo-like kinase 2 (PLK2) is a serine/threonine protein associated with the regulation synaptic plasticity centriole duplication. We identify as crucial early-response gene lipopolysaccharide (LPS)-stimulated cells. Knockdown or inhibition remarkably attenuates proinflammatory factors cells by suppressing inhibitor nuclear factor kappa B subunit beta (IKKβ)-nuclear (NF)-κB pathway. heat shock 90 alpha (HSP90α), regulator IKKβ activity, novel substrate. pharmacological HSP90α abolishes PLK2-mediated transcriptional activity inflammatory activation. Furthermore, phosphoproteomic analysis pinpoints Ser252 Ser263 on phosphorylation targets PLK2. Lastly, conditional knockout dramatically ameliorates subsequent loss an intracranial mouse Parkinson's disease (PD) model. The present study reveals that promotes IKKβ-NF-κB pathway.Graphical abstract

Language: Английский