Evaluation of ERK Pathway Contributions to 5-OXO-ETE and Hydroxystearic Acid-mediated Autophagy Dysfunction

Parkinson’s disease (PD) is the most common motor disease and the second most common neurodegenerative disease. Key hallmarks of the disease are the loss of dopaminergic neurons in the substantia nigra and autophagy dysfunction. Autophagy is a cellular process responsible for the degradation of organelles, macromolecules and toxic protein aggregates. In the case of PD, toxic alpha-synuclein aggregates build up and are the substrate for autophagic degradation. As a result, modulation of autophagy could prove to be an effective target for the treatment of PD. However, to date, there have been no clinical treatments that harness autophagy for therapeutic benefit. Therefore, we seek to identify endogenous small lipid molecules that act as signaling mediators for autophagy. Our recent unbiased lipidomic screen has revealed that 5-OXO-ETE and hydroxystearic acid are potent inhibitors of autophagy. To determine the mechanism of action, we are evaluating the contribution of key molecular signaling pathways for these two lipids. Our investigation has uncovered that ERK signaling is altered by the lipids and thus may be important in autophagy inhibition. The ultimate goal of this work is to identify novel targets for therapeutic modulation of autophagy in Parkinson’s disease and other maladies.