Autophagy Disruptions Associated With Altered Optineurin Expression in Extranigral Regions in a Rotenone Model of Parkinson's Disease.

Abstract

The motor features of Parkinson's disease (PD) primarily result from a lesion to the nigrostriatal dopamine system. Numerous non-motor symptoms occur in PD, many of which are postulated to stem from pathology outside of the nigrostriatal dopamine system. Perturbations to protein trafficking, disruption of mitochondrial integrity, and impaired autophagy have repeatedly been implicated in dopaminergic neuron cell death. Previously, we demonstrated that multiple markers of autophagy are disrupted in a rotenone model of PD, with alterations occurring prior to an overt lesion to the nigrostriatal dopamine system. Whether these events occur in extra-nigral nuclei in PD and when relative to a lesion in the nigrostriatal dopamine system are generally unknown. The primary goal of these studies was to determine whether autophagy disruptions, in non-dopaminergic neuronal populations occur in an environmental model of PD utilizing a mitochondrial toxin. Here, we utilized the rat rotenone PD model, with sampling time-points before and after an overt lesion to the nigrostriatal dopamine system. In analyzing autophagy changes, we focused on optineurin (OPTN) and the autophagy marker, LC3. OPTN is an autophagy cargo adapter protein genetically linked to amyotrophic lateral sclerosis and glaucoma. In the present study, we observed OPTN enrichment in all PD-relevant brain regions examined. Further, alterations in OPTN and LC3 expression and colocalized puncta suggest specific impairments to autophagy that will inform future mechanistic studies. Thus, our data suggest that autophagy disruptions may be critical to PD pathogenesis in non-dopaminergic neurons and the onset of non-motor symptoms.