The ubiquitin–proteasome system and autophagy mutually interact in neurotoxin-induced dopaminergic cell death models of Parkinson's disease

Precise control of the two major proteolysis systems [i.e. ubiquitin–proteasome system (UPS) and autophagy–lysosomal pathway (ALP)] is important for proper cell function. Here, we explored whether UPS and ALP affect each other in two neurotoxin-based cell death models of Parkinson's disease. Monitoring UPS and ALP activity using their specific reporter plasmids revealed that treatment with the neurotoxin MPP⁺ or the neurotoxin 6-OHDA decreased proteasome activity in dopaminergic MN9D cells. Interestingly, ALP inhibition relieved or potentiated the decrease in proteasome activity induced by the two toxins. Moreover, suppression of proteasome activity promoted 6-OHDA-induced excessive autophagic flux, potentiating ALP dysregulation. In contrast, MPP⁺-induced impairment of ALP was alleviated by proteasome inhibition. These findings suggest a dynamic interplay between UPS and ALP operating in MN9D cells under two distinct toxin-mediated cell death pathways.