Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model

Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model; Shiang L (Max), Jarmon Lees, Haoxiang Zhang, Li Li, Mirella Dottori, Alice Pebay, Louise Corben, Martin Delatycki, Stephen Wilcox, Jeffrey Pullin, Jarny Choi, Davis McCarthy, Jill Napierala, Marek Napierala. bioRxiv 2026.10.06.757136; doi:10.64898/2026.10.06.757136 

 Bulk RNA sequencing of all three isogenic pairs revealed loss of extracellular matrix programs and activation of stress response pathways. The top differentially expressed gene was MEG3, a maternally imprinted long noncoding RNA, which was consistently upregulated across all three isogenic pairs. MEG3 sits within the imprinted 14q32 DLK1-DIO3 locus, whose maternally expressed noncoding transcripts were co-ordinately de-repressed in FRDA autonomic neurons. Competitive gene-set testing of 43 imprinted genes across 20 domains showed this to be specific to 14q32: no other imprinted domain was co-ordinately altered. Together, these findings establish hyperexcitability of autonomic neurons as a cell autonomous consequence of frataxin deficiency, accompanied by mitochondrial dysfunction. This provides a cellular basis for the increased sympathetic tone observed in clinical studies.

Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model