Image: WikipediaFriedreich’s ataxia, the most common inherited ataxia, is an autosomal recessive disorder that causes progressive damage to the nervous system and heart. There are currently few treatment options and most people with the disease are ultimately confined to a wheelchair and many die as young adults.
The genetic disorder results in decreased synthesis of the protein frataxin which is essential for mitochondrial function, including oxidative phosphorylation and iron homeostasis. Reduced frataxin synthesis has been linked to abnormally expanded GAA repeats in the first intron of the frataxin gene – the length of the GAA repeats correlates with disease severity. The unusual DNA structure that results from these repetitions is believed to recruit histone deacetylases (HDACs), leading to gene silencing. In 2006, a team from the Scripps Research Institute identified N1-(2-aminophenyl)-N7-phenylheptanediamide (compound 1) as an HDAC inhibitor that reverses frataxin gene silencing in primary lymphocytes from people with Friedreich’s ataxia. Later work by the group showed that a related compound, N1-(2-aminophenyl)-N7–p-tolylheptanediamide (compound 2), increased frataxin production in a mouse model of Friedreich’s ataxia. Although it was known that effects of the two compounds were linked to HDAC inhibition, it was not clear which particular HDAC was involved.
Working with Repligen scientists, the Scripps team have now identified HDAC3 as the key enzyme involved in Freidreich’s ataxia. Incubation of a trifunctional activity-based probe (compound 3) with a panel of class I and class II recombinant HDAC enzymes followed by addition of a fluorescent dye using click chemistry and subsequent gel electrophoresis showed that HDAC-3 was the only high affinity target for the probe. HDAC3 was also shown to be the preferred cellular target of the probe. The team hope that a better understanding of the mechanism of action of these compounds will provide new insights into the progression of Friedreich’s ataxia and other trinucleotide repeat disorders, such as Huntington’s disease, and improve the chances of effective treatments. Compound 1 has already been shown to improve physical appearance and motor function in a mouse model of Huntington’s disease.
The study is published in the journal Chemistry & Biology.