ABSTRACT
Friedreich’s Ataxia (FRDA) is the commonest hereditary form of ataxia affecting the Western European population. FRDA is an autosomal recessive neurodegenerative disorder caused by an intronic GAA repeat expansion within the FXN gene; the 96% of the patients are homozygous, while the remaining 4% are compound heterozygous carrying the GAA repeat mutation on one allele and point mutations on the other one. FRDA first symptoms appear at young age during the firsts two decades of life. The clinical features include progressive gait and limb ataxia, dysarthria, muscle weakness, peripheral sensory neuropathy, pes cavus, and scoliosis. FRDA is a multi-systemic disorder; therefore, patients develop non-neurological signs, such as hypertrophic cardiomyopathy, diabetes, and urological problems.
The genetic mutation leads to a progressive decrease of the mitochondrial protein frataxin, which resides in the inner mitochondrial membrane. Frataxin is a small essential protein of 210 amino acids whose structure in the C-terminal region is conserved in all organisms from bacteria to human. Mitochondrial dysfunction in FRDA is strictly linked to frataxin functional role in the iron biogenesis. Frataxin deficiency leads to impairment ISCs formation which in turn affects the ISC-containing proteins (including complex I, II, and III of the mitochondrial electron transport chain and aconitase). The pathogenic mechanism triggered by the reduced production of frataxin leads to the generation of oxidative stress, mitochondrial energy imbalance and an increase in lipid peroxidation, as shown in cerebellar granule neurons (CGNs), and mouse fibroblasts. Lipid peroxidation has been proven to be one of the causes inducing neuronal death, as by pre-treating the cells with poly-unsaturated fatty acids (dPUFAs), the phenotype was rescued. In this chapter we review the current knowledge on the mitochondrial dysfunction in FRDA.
