Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia

Pernaci C, Johnson A, Gillette S, Warden AS, McCormick C, Weiser-Novak S, Ramirez G, Broersma EH, Mishra P, Sivakumar A, Cherqui S, Coufal NG. Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia. Nat Commun. 2025 Nov 29;17(1):81. doi: 10.1038/s41467-025-66710-y. PMID: 41318543; PMCID: PMC12770375. 

 In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.