Friedreich's Ataxia

Friedreich's ataxia, abbreviated FRDA or FA, is a rare genetic disorder that causes progressive neurological damage and motor problems. It is caused by an over-amplification of the GAA trinucleotide repeat sequence in intron 1 of the FRDA gene. Cardiomyopathy due to Friedreich's ataxia (FA), the most common autosomal recessive ataxia, is a more serious complication for which there is no effective treatment.

Pathogenesis of Friedreich's Ataxia

Friedreich's ataxia (FA) is an autosomal recessive disorder caused by mutations in the FXN gene encoding the mitochondrial frataxin protein located on chromosome 9. Patients with FA can have trinucleotide repeats of more than 1000 copies of GAA and it has been shown that the number of these repeats is inversely proportional to the age of disease onset. Common features of this disease are loss of positional awareness, muscular dystrophy, hypertrophic cardiomyopathy, and diabetes mellitus.

Iron Metabolism Dysregulation in Friedreich's Ataxia

In Friedreich's ataxia (FA), mutations of the mitochondrial protein frataxin (FXN) lead to impaired Fe-S cluster biogenesis which further leads to disruption of iron metabolism along with increased mitochondrial iron contents. Excessive accumulation of iron leads to the production of reactive oxygen species (ROS), causing lipid peroxidation and cell death. Mutation of frataxin has also been shown to impair the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key player for antioxidant gene expressions, into the nucleus, which not only impairs antioxidant response, but also contributes to the ROS production.

Nrf2 activity in a healthy patient and an FRDA patient. This figure demonstrates the effect of omaveloxolone therapy on Nrf2 activity in an FRDA patient.

Nrf2 As a New Target for Friedreich's Ataxia Treatment

Nrf2 regulates the expression of many genes involved in antioxidant defense by activating enzymes that constitute the phase II response. Thus, changes in intracellular redox status can transiently alter Nrf2 activity, and its activation has been shown to counteract many of the pathological mechanisms associated with a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia. It was shown that the use of Nrf2 inducers significantly upregulated Nrf2 and its target genes in frataxin-deficient motor neurons helped stabilize the redox environment in FA by targeting reduced glutathione (GSH) supplementation and attenuating reactive oxygen species (ROS)-related damage, thereby ultimately counteracting neurodegeneration.

The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia ^[2].

In FA, oxidative stress is exacerbated by dysregulation of cellular antioxidant defenses due to frataxin deficiency, making Nrf2 activation an increasingly attractive strategy for treating this disease. nrf2 could be used as a therapeutic target in FA and its induction as a promising approach to prevent or slow down the pathological changes observed in this disease.

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Although there is no energy-efficient cure or treatment for Friedreich's ataxia. However, it has been shown that disturbances in iron metabolism are an important cause of neuronal cell death in the disease, and in the meantime, scientists are exploring ways to increase frataxin levels and regulate iron metabolism through drug therapy, genetic engineering, and protein delivery systems. Protheragen offers research services related to iron metabolism disorders and neurodegenerative diseases, helping clients to conduct in-depth research into the etiology of Friedreich's ataxia and providing new therapeutic ideas for the prevention and treatment of neurodegenerative diseases. If you are interested in the services we offer, please contact us for more information.