Nrf2 dysfunction in patient-derived cell lines in a new model of sporadic Parkinsons disease

We recently reported a novel patient-derived cellular model of Parkinson’s disease generated from biopsies of the olfactory mucosa, the organ of smell in the nose. Olfactory neurosphere-derived (hONS) cells from Parkinson’s disease patients had reduced metabolic functions already associated with disease, including reduced levels of the important antioxidant molecule glutathione. Transcriptomic analysis of patient and Control hONS cells identified the signalling pathway surrounding NRF2, the major transcriptional regulator of the antioxidant response, as being highly differentially expressed in Parkinson’s disease. We have shown that activation of the NRF2 pathway in Parkinson’s disease hONS cultures restored metabolic function to Control levels, thereby validating NRF2 as a genuine therapeutic target. Paradoxically, transcriptomic analysis of hONS cells after NRF2 pathway activation revealed increased dysregulation of the NRF2 pathway in treated Patient-derived cells. We are now investigating the functional consequences of dysregulated NRF2 activation in Patient-derived hONS cells. Specifically, we are pursuing the recently described link between NRF2 and p62, an important regulator of autophagy, a cellular process implicated in many neurodegenerative diseases. Our results demonstrate that Patient cells can respond to NRF2 activation but that this may elicit a different cellular outcome than that of Control cells. This may be an important factor when developing new therapeutics.