Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Marta Medina-Carbonero,Jordi Tamarit,Joaquim Ros,Elena Britti,Arabela Sanz-Alcázar,Elisa Cabiscol,Fabien Delaspre

doi:10.1007/s00018-021-04100-5

Marta Medina-Carbonero, Jordi Tamarit + Show 5 more

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https://doi.org/10.1007/s00018-021-04100-5

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Abstract

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense mutation in the other allele. One of these mutations, FXNI154F, was reported to result in decreased content of mature frataxin and increased presence of an insoluble intermediate proteoform in cellular models. By introducing this mutation into the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the consequences of this pathological point mutation in vivo. We have observed that FXNI151F homozygous mice present low frataxin levels in all tissues, with no evidence of insoluble proteoforms. Moreover, they display neurological deficits resembling those observed in FA patients. Biochemical analysis of heart, cerebrum and cerebellum have revealed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in antioxidant defenses. These mitochondrial alterations are more marked in the nervous system than in heart, precede the appearance of neurological symptoms, and are similar to those observed in other FA models. We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.

Highlights

Friedreich Ataxia (FA) is a rare, inherited recessive disease first described by Nikolaus Friedreich, a German pathologist, in 1863
Frataxin has been shown to localize to the mitochondria, where it regulates the activity of cysteine desulfurase, an enzyme required for the biosynthesis of iron–sulfur clusters [5]
In the present work we have analyzed the consequences of the FXN I151F mutation in mice, which is equivalent to the human I154F pathological mutation

Summary

Introduction

Friedreich Ataxia (FA) is a rare, inherited recessive disease first described by Nikolaus Friedreich, a German pathologist, in 1863. FA is characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception [1]. Most FA patients present hypertrophic cardiomyopathy, cardiac dysfunction being the leading cause of death [2]. The. Decreased expression of frataxin is associated with mitochondrial dysfunction, iron and calcium imbalance, and increased oxidative stress. The function of frataxin and the mechanisms causing such cellular disturbances are not completely understood. Frataxin has been shown to localize to the mitochondria, where it regulates the activity of cysteine desulfurase, an enzyme required for the biosynthesis of iron–sulfur clusters [5]. It is generally accepted that frataxin activates iron–sulfur biogenesis in eukaryotes

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