New project: Identification of the E3 ligase that ubiquitinates frataxin

Identification of the E3 ligase that ubiquitinates frataxin
Principal researcher: Dr Roberto Testi, Department of Experimental
Medicine,
University of Rome, 'Tor Vergata,' Italy
Scientific summary
Understanding whether and how frataxin is normally degraded might
provide insights
on possible strategies aimed at preventing frataxin degradation in FRDA
patients,
thus allowing frataxin accumulation and increasing frataxin
bioavailability. We
observed that frataxin is degraded via the ubiquitin-proteasome system
and that by
preventing the degradation process, frataxin levels in fact rise in FRDA
cells. We also
identified the lysine responsible for ubiquitination. In fact, a
frataxin lacking the critical
lysine cannot be ubiquitinated and has a longer half life. We now plan
to identify the
E3 ligase(s) that interacts with frataxin and mediates frataxin
ubiquitination. This
information should reveal new potential pharmacological targets for
FRDA.
Lay summary
FRDA is caused by the low levels of the protein frataxin in cells of
affected
individuals, due to scarce production. Since normally all proteins are
constantly
produced and degraded, one way to possibly increase frataxin levels is
to slow down
its degradation. We therefore started to understand the mechanisms by
which
frataxin is degraded in human cells. The aim of this project is to
refine our
understanding of the modalities of frataxin degradation and to further
elucidate the
molecular mechanisms. This information could be instrumental in
developing new
therapeutic approaches focused on preventing frataxin degradation.
This project is co-funded with the Friedreich's ataxia Society Ireland
(FASI).
For more support or information please contact: Ataxia UK, Lincoln
House,
Kennington Park, 1 – 3 Brixton Road. London SW9 6DE
Website: www.ataxia.org.uk.
Helpline: 0845 644 0606 Tel: +44 (0)20 7582 1444 Fax: +44 (0)20 7582
9444
Email: helpline@ataxia.org.uk.