Parkinson's disease is associated with neuroinflammation and the death of dopaminergic neurons. In Science Signaling, Hu et al. identify the kinase MEK1 as a target of the mitochondrial protease Omi. Omi is a stress-response protein that is released into the cytoplasm. Loss of Omi function is associated with neurodegeneration in Parkinson's disease in humans and in the mouse mnd2 model. Mutation or knockdown of the gene encoding Omi in glial cells leads to greater abundance of MEK1 and phosphorylation of the downstream kinases Erk1 and Erk2, which is also observed in the brains of mnd2 mice. This heightened Erk activation elicits enhanced production of inflammatory mediators, including TNF, IL-1β and reactive oxygen species. Supernatants from such Omi-deficient glial cells are toxic to primary neurons. Thus, the Omi protease normally acts as a brake to prevent excessive activation of the MEK1-Erk1/2 signaling pathway and diminish glial pro-inflammatory responses in the brain.

Sci. Signal. 5 (21 August 2012) doi:10.1126/scisignal.2002946