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
Parkinson's disease.

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.

Although 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

"We 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.

Similarly, 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 mutations."          -AD