Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting

Abstract

Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disorder caused by a GAA repeat expansion within the FXN gene, leading to reduced frataxin levels. This deficiency results in mitochondrial dysregulation, oxidative stress, and progressive cell death. Currently, only one approved treatment exists for FRDA in the United States, Canada, and the European Union, which improves neurological outcomes but has not been fully evaluated for broader disease symptoms. Therefore, identifying new therapeutic targets remains essential. Sphingolipids are increasingly recognized for their roles in neurodegeneration with emerging evidence indicating their dysregulation in FRDA. Here, we investigate whether sphingolipid-metabolizing enzymes are similarly affected and assess the therapeutic potential of targeting them. Our findings demonstrate that these enzymes are dysregulated across multiple FRDA models. Importantly, their modulation in vitro and in vivo significantly reduces mitochondrial dysfunction, enhances frataxin expression, and improves key pathological features of the disease, highlighting sphingolipid metabolism as a promising therapeutic target for FRDA.