Journal
FEBS LETTERS
Volume 596, Issue 22, Pages 2898-2913Publisher
WILEY
DOI: 10.1002/1873-3468.14479
Keywords
6-OHDA; autophagy-lysosomal pathway; MPP+; neuronal cell death; Parkinson's disease; ubiquitin-proteasome system
Funding
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT, Korean Government [NRF-2021R1A2C1005469]
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This study reveals a dynamic interplay between ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) in neurotoxin-based cell death models of Parkinson's disease, indicating their involvement in regulating cell death pathways.
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.
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