Microglia from Friedreich Ataxia patients are intrinsically primed for neuroinflammation

Abstract

Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive loss of cerebellar and proprioceptive neurons that control movement and coordination. In most patients, FRDA is caused by homozygous GAA trinucleotide repeat expansions in the first intron of the frataxin (FXN) gene, resulting in reduced expression of frataxin, a mitochondrial protein essential for biogenesis of iron-sulfur clusters and mitochondrial function. Although recent therapeutic advances have provided modest clinical benefit, effective disease-modifying treatments remain lacking. Increasing evidence indicates that microglial cell dysfunction contributes to FRDA pathogenesis, highlighting these cells as potential therapeutic targets. However, the molecular mechanisms underlying FXN-deficient microglial dysfunction remain poorly understood. Here, we show that microglia generated from FRDA patient-derived iPSCs exhibit a cell-autonomous pro-inflammatory phenotype in the absence of exogenous inflammatory stimuli. This phenotype is characterized by coordinated activation of immune transcriptional programs, dysregulated secretion of neuroinflammatory proteins, impaired autophagy-lysosomal function, and activation of inflammasomes pathways involving NLRP2 and NLRP3. These findings demonstrate that FXN deficiency is sufficient to induce intrinsic microglial activation and identify molecular pathways that may represent attractive targets for future FRDA therapies.