A protein called RNF126 mediates the degradation of the frataxin protein in cells of people with Friedreich’s ataxia, a new study presented at IARC 2017 showed. Its researchers suggest that targeting this protein may be a way of treating the disease, as RNF126 inhibition allowed frataxin to accumulate in cells.
The study, “E3 ligase RNF126 directly ubiquitinates frataxin, promoting its degradation: identification of a potential therapeutic target for Friedreich Ataxia,” was presented Wednesday at the 2017 International Ataxia Research Conference by Monica Benini with the University of Rome, Tor Vergata. The conference runs in Pisa, Italy, through Sept. 30.
Unusually low levels of frataxin, a mitochondrial protein, is the underling cause of Friedreich’s ataxia. The disease currently has no effective treatment, and research aiming to slow or halt progression is focused on restoring frataxin levels to normal — what is known as physiological levels.
In previous studies, researchers identified the ubiquitin-proteasome system as the major pathway degrading frataxin in cells. Proteins targeted for degradation via this system first are attached to one or multiple ubiquitin molecules, which send a signal to the proteasome, which ultimately degrades proteins. (In healthy people, proteasome degrades damaged or unwanted proteins.)
A special class of protein, called E3 ubiquitin ligase, is key in preparing a protein for degradation.
As such, inhibiting the E3 ubiquitin ligase may be a way to increase cellular levels of frataxin and prevent its degradation.
Researchers set out to identify the E3 ligase that ubiquitinates — or tags for destruction — the frataxin protein by decreasing the expression of genes coding for more than 600 E3 ligases using small interfering RNAs (siRNA).
siRNAs induce short-term silencing of protein-coding genes, so researchers can identify which genes, once silenced, lead to an increase in frataxin protein levels.
In human cells, frataxin is synthesized first as a precursor protein, and then, upon import into the mitochondria, is processed to its final, mature form.
Results showed that RNF126 is the E3 ubiquitin ligase targeting frataxin, interacting with frataxin in its precursor state to promote its tagging and consequent degradation at the proteasome.
“We isolated one gene named RNF126 that constitutively promotes frataxin expression when silenced in cells,” Benini said in her presentation. “Silencing of RNF16 increases frataxin stability.”
Depleting RNF126 in cells derived from Friedreich’s ataxia patients led to increased frataxin levels in those cells.
“The inhibition of RNF126 or even better of the specific interaction between RNF126 and the frataxin precursor could be an attractive therapeutic strategy based on a new identified target,” Benini said.
“All these findings were recently published and we hope it opens a new way for a therapeutic approach,” she concluded.
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