Objective: Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. Methods: Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study. Results: FXNI 154F and FXNG 130V missense mutations decrease FXN81–210 levels compared with FXNWT, FXNR 165C, and FXNW 155R, but do not block its association with mitochondria. FXNI 154F and FXNG 130V also impair FXN maturation and enhance the binding between FXN42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG 130V. Finally, clinical data from patients with FXNG 130V and FXNI 154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia. Interpretation: These data suggest that the effects on processing associated with FXNG 130V and FXNI 154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.
ASJC Scopus subject areas
- Clinical Neurology