Preventing the ubiquitin–proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia

Abstract

Friedreich's ataxia (FRDA) is a devastating orphan disease, with no specific treatment. The disease is caused by reduced expression of the protein frataxin, which results in mitochondrial defects and oxidative damage. Levels of residual frataxin critically affect onset and progression of the disease. Understanding the molecular mechanisms that regulate frataxin stability and degradation may, therefore, be exploited for the design of effective therapeutics. Here we show that frataxin is degraded by the ubiquitin-proteasome system and that K(147) is the critical residue responsible for frataxin ubiquitination and degradation. Accordingly, a K(147)R substitution generates a more stable frataxin. We then disclose a set of lead compounds, computationally selected to target the molecular cleft harboring K(147), that can prevent frataxin ubiquitination and degradation, and increase frataxin levels in cells derived from FRDA patients. Moreover, treatment with these compounds induces substantial recovery of aconitase activity and adenosine-5'-triphosphate levels in FRDA cells. Thus, we provide evidence for the therapeutic potential of directly interfering with the frataxin degradation pathway.

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

“…Previously, it has been observed that DOX increases the activity of the UPS (43), and in this line of investigation we observed that DOX-mediated degradation of FXN involves the UPS. To further explain our discovery, findings by Rufini et al (47) have observed that lysine 147 may be critically involved in FXN ubiquitination and degradation. Our findings indicate that DOX alters the subcellular localization of FXN, and thus future work should focus on identifying the NH 2 -terminal amino acid residues in FXN that are altered by DOX, as these sites are highly significant for maturation and mitochondrial localization.…”

The alteration of the C‐terminal region of human frataxin distorts its structural dynamics and function

“…From a structural point of view, protein motions are involved in very different processes: rotamer selection, backbone rearrangements, local unfolding and even global unfolding/refolding transitions. In this context, changes in the dynamics of the native state can affect protein-protein and protein-substrate interactions and in vivo stability that, in the case of FXN, is particularly relevant in FRDA [13,33].…”

Emerging Therapies in Friedreich’s Ataxia

“…A ubiquitin competing molecule, NSC620299, decreased frataxin degradation within the cell; however, further study must be completed on the effect within the mitochondria. Ubiquitin competitors show potential promise as treatment of FRDA [45]. …”