Article

Friedreich ataxia (FRDA) is the most common hereditary autosomal recessive
ataxia, but is also a multisystemic condition with frequent presence of
cardiomyopathy or diabetes. It has been linked to expansion of a GAA-triplet
repeat in the first intron of the FXN gene, leading to a reduced level of
frataxin, a mitochondrial protein which, by controlling both iron entry and/or
sulfide production, is essential to properly assemble and protect the Fe-S
cluster during the initial stage of biogenesis. Several data emphasize the role
of oxidative damage in FRDA, but better understanding of pathophysiological
consequences of FXN mutations has led to develop animal models. Conditional
knockout models recapitulate important features of the human disease but lack the
genetic context, GAA repeat expansion-based knock-in and transgenic models carry
a GAA repeat expansion but they only show a very mild phenotype. Cells derived
from FRDA patients constitute the most relevant frataxin-deficient cell model as
they carry the complete frataxin locus together with GAA repeat expansions and
regulatory sequences. Induced pluripotent stem cell (iPSC)-derived neurons
present a maturation delay and lower mitochondrial membrane potential, while
cardiomyocytes exhibit progressive mitochondrial degeneration, with frequent dark
mitochondria and proliferation/accumulation of normal mitochondria. Efforts in
developing therapeutic strategies can be divided into three categories: iron
chelators, antioxidants and/or stimulants of mitochondrial biogenesis, and
frataxin level modifiers. A promising therapeutic strategy that is currently the
subject of intense research is to directly target the heterochromatin state of
the GAA repeat expansion with histone deacytelase inhibitors (HDACi) to restore
frataxin levels.
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