Friedreich’s Ataxia (FRDA) is a devastating degenerative disease with no specific therapy. It is passed by autosomal recessive inheritance and affects 1:30,000 individuals in Caucasian populations. Symptoms appear in the first decade of life and include progressive and unremitting lack of movement coordination, leading to complete inability, and dilated cardiomyopathy leading to congestive heart failure, the most common cause of premature death. FRDA is due to the insufficient transcription of the gene coding for the mitochondrial protein frataxin. Reduced cellular levels of frataxin cause impaired mitochondrial function and increased sensitivity to oxidative stress, leading to accelerated cell death in critical tissues.
Severity of the disease critically depends on residual frataxin levels. Therapeutic efforts are mostly focused on increasing cellular frataxin . We found that frataxin is normally degraded by the ubiquitin-proteasome system. We identified the lysine responsible for the ubiquitination of frataxin and, by computational screening followed by experimental validation, we identified and validated a series of small molecules, called ubiquitin-competing molecules (UCM), that prevent frataxin ubiquitination and induce frataxin accumulation in cells derived from FRDA patients. Moreover, treatment with UCM partially rescues aconitase and ATP production defects in cells derived from FRDA patients.
Our goal is two fold: 1) submit a set of leads we already identified, as well as their new and more complex derivatives, to preclinical testing in FRDA mice 2) identify the E3 ligase that is responsible for frataxin ubiquitination, and investigate the possibility to use it as a druggable target for small molecules to prevent frataxin degradation.
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