Charakterystyka zmian elektrофizjologicznych i transkryptomowych w neuronach pochodnych od pacjentów z zespołem CHAMP1
Characterization of Electrophysiological and Transcriptomic Alterations in Patient-Derived Neurons from CHAMP1 Syndrome
W skrócie
[Preprint - wstępne wyniki] Badacze zbadali neurony pochodzące od pacjentów z mutacjami genu CHAMP1, które powodują niepełnosprawność intelektualną, opóźnienie rozwojowe i autyzm. Odkryli, że te mutacje zaburzają funkcję neuronów, zmniejszając zdolność wywoływania impulsów elektrycznych, pogarszając działanie kanałów jonowych oraz zmniejszając kontakty między neuronami. Wyniki sugerują, że mutacje CHAMP1 wpływają na wiele procesów rozwojowych mózgu, co może pomóc w opracowaniu nowych terapii dla pacjentów z tym zaburzeniem.
Oryginalny abstract (angielski)
Mutations in chromosome alignment maintaining phosphoprotein 1 (CHAMP1) have been linked to neurodevelopmental disorders characterized by intellectual disability, developmental delay, and autism spectrum disorder. However, the cellular and electrophysiological mechanisms by which CHAMP1 mutations disrupt human neuronal development remain poorly understood. In the present study, we used patient-derived induced pluripotent stem cells (iPSCs) carrying two pathogenic CHAMP1 mutations and generated neural progenitor cells (NPCs) and excitatory neurons to investigate the effects of each mutation on neuronal maturation and function, DNA repair, and gene expression. Proliferative capacity and DNA repair dysfunction operate in a CHAMP1 dose-dependent manner. Whole-cell patch-clamp electrophysiology revealed that CHAMP1 mutant neurons exhibit significant alterations in intrinsic membrane properties during early developmental stages, including depolarized resting membrane potential, reduced action potential firing, and impaired waveform kinetics. These functional deficits were accompanied by reduced sodium and potassium current densities, suggesting impaired ion channel accumulation during neuronal maturation. Furthermore, recordings of spontaneous excitatory postsynaptic currents indicated altered synaptic activity and reduced proportions of synaptically active neurons. Morphological analyses revealed deficits in neurite outgrowth and branching, consistent with delayed neuronal maturation. Single-nucleus transcriptomic profiling further revealed delayed developmental trajectories and mutation-specific dysregulation of synaptic gene programs enriched for autism, ADHD, and epilepsy risk genes. Together, these findings demonstrate that CHAMP1 mutations disrupt multiple aspects of neuronal development, including homologous recombination (HR) dysfunction in NPCs, membrane excitability, ion channel function, and synaptic connectivity. Our results provide insights into the neurobiological consequences of CHAMP1 mutations and establish patient-derived neurons as a platform to investigate cellular pathophysiology and potential therapeutic strategies for CHAMP1-associated neurodevelopmental disorders.