Transcriptomic analysis of iPSC-derived microglia from Friedreich Ataxia patients and matching isogenic controls
Friedreich ataxia (FA) is a neurodegenerative disease that causes progressive loss of specific neuronal populations, including cerebellar neurons involved in control of movement and equilibrium. FA is an autosomal recessive disorder caused by homozygous GAA trinucleotide repeat expansions in the first intron of the frataxin (FXN) gene, resulting in impaired transcription and decreased expression of the FXN protein. FXN is a mitochondrial protein involved in the biogenesis of iron-sulfur clusters and energy production. Its deficiency causes loss of activity of multiple Fe/S enzymes, altered iron metabolism, and broad mitochondrial phenotypes (Campuzano et al., 1997; Llorens et al., 2029; Reetz et al., 2025; Ristow et al., 2000). There is currently no effective cure for this debilitating neurodegenerative condition. Little is known about the molecular mechanisms underlying the dysregulation of neuroinflammatory mechanisms in FXN-deficient microglia. In this study, we characterized the transcriptome and secretome changes associated with FXN deficiency using microglia generated from FA patient-derived iPSCs and matching isogenic controls.