Neuronal activity-dependent gene dysregulation in C9orf72 i3Neuronal models of ALS/FTD pathogenesis.

Abstract

The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9ORF72 (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K⁺ channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared with healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.NEW & NOTEWORTHY A recent study using iPSC-derived cortical neurons reveals how neuronal activity drives gene dysregulation in C9ORF72-linked ALS/FTD. We uncover synaptic dysfunction, peroxisomal dysregulation, and NPAS4-linked transcriptional shifts, highlighting key disease-modifying pathways. Could these insights pave the way for new therapeutic targets? Explore our research and generate your own discoveries using our interactive dataset included in the link in the article.