Thursday, September 12, 2013
Box 1. Targeting mitophagy in Parkinson's disease.
Mitophagy is the selective and programmed destruction of
damaged mitochondria in a cell. The process can protect cells, including
neurons, from death. Several genes encoding the proteins that orchestrate
mitophagy, including PTEN induced putative
kinase 1, Parkin and F-box protein 7,
are mutated in familial forms of
Parkin (PARK2) and F-box
protein 7 (FBXO7) are both E3
ubiquitin ligases that are recruited to damaged mitochondria in a PTEN induced
putative kinase 1
(PINK1)-dependent fashion and are activated in response to mitochondrial
stress. Mitophagy depends on the enzymatic activation of PARK2 and FBXO7.
the Shokat group used
kinetin to activate PINK1 and mitophagy, separate research groups from the U.K.
and Canada are exploring alternative therapeutic targets.
A team of
British researchers led in part by Helene Plun-Favreau, a senior lecturer in
the Department of Molecular Neuroscience at the UCL Institute of Neurology, recently reported that, similar to PARK2, FBXO7
plays a role in mitophagy downstream of PINK1.3
are planning to do some compound screening in the near future to try and
correct or improve mitophagy. One possibility would be to try to improve PARK2
and/or FBXO7 recruitment to damaged mitochondria," she said.
a Canadian team led in part by Edward Fon, an associate professor of neurology
and neurosurgery at McGill University
and director of the McGill Parkinson Program, recently reported the first
structure of Park2, demonstrating with multiple structural methods that the protein
adopts an autoinhibited conformation.6
Mutation of the protein to disrupt formation of this conformation
increased the activity of the ligase and its recruitment to mitochondria
compared with no mutation. Fon told SciBX, "We are
now looking for small molecules that disrupt this autoinhibitory interaction.
We are setting up screens to find small molecules that will mimic the