Researchers Find Novel Therapeutic Strategy for Friedreich’s Ataxia

Researchers at the University of Rome “Tor Vergata” in Italy and Fratagene Therapeutics Ltd. in Ireland recently revealed a novel therapeutic strategy for Friedreich’s ataxia based on specific small molecules. The study was published in the journal Neurobiology of Disease and is entitled “Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconite defect in Friedreich ataxia cells.”

Friedreich’s ataxia is a rare inherited neurodegenerative disease that affects children and young adults. It is characterized by progressive damage of the nervous system with degeneration of the spinal cord and peripheral nerves that leads to muscle weakness, sensory loss, balance deficits and loss of voluntary coordination of muscle movements. Patients often develop cardiomyopathy, a condition where the heart’s muscle (myocardium) function is compromised and one of the main causes of premature death in these patients. The disorder leads to progressive disability, dependence on a wheelchair and reduced life expectancy. It is estimated that Friedreich’s ataxia has a prevalence of 1:50,000 in the Caucasian population. There is currently no effective treatment and patients die prematurely.

Friedreich’s ataxia is caused by a mutation in a gene called frataxin (FXN), which leads to a reduction in messenger RNA and subsequent reduction in frataxin protein expression, causing mitochondrial dysfunction, disruption of iron homeostasis and ultimately cell death.

The lower the frataxin levels, the higher the severity of disease progression, and as such, several therapeutic strategies aim to increase frataxin protein levels in these patients, either by promoting FXN gene expression or by preventing frataxin protein from being degraded in the cells. This study focused on the latter strategy.

It was previously reported that a considerable quantity of frataxin protein precursor is degraded in the cell by a system called ubiquitin/proteasome, the most important system for intracellular protein degradation. It was also shown that small specific molecules can dock on the frataxin ubiquitination site (at lysine 147) and prevent frataxin ubiquitination (addition of ubiquitin molecules in lysine residues marking the protein for degradation) and subsequent degradation. These potentially therapeutic small molecules were called compounds ubiquitin-competing molecules (UCM) and can lead to an increase in frataxin levels.

In this study, the search for effective UCM was expanded and new and more potent molecules were found. These “second-generation” UCM were found to physically interact with frataxin and prevent its ubiquitination, promoting an increase in frataxin levels.

UCM were found to be inefficient in frataxin mutants, which are resistant to ubiquitination due to a mutation in lysine 147, suggesting that the UCM activity occurs by inhibiting ubiquitination on frataxin lysine 147 site. Researchers also discovered that UCM not only promotes frataxin accumulation in the cells, but also restores aconitase activity (an iron-sulfur protein, highly dependent on frataxin levels and whose activity is decreased in Friedreich’s ataxia) in cells derived from patients, strongly supporting their potential therapeutic application.

The research team concluded that UCM directly binds to the frataxin protein, preventing its ubiquitination and degradation, and leading to an increase in frataxin levels. The team believes that UCM can represent a novel therapeutic strategy for Friedreich’s ataxia.