NAC1, A POZ/BTB protein interacts with Parkin and may contribute to Parkinson's disease.
Loss-of-function in the Parkin protein is thought to play a part in causing neuronal cell death in patients with Parkinson's disease. This study explores the effect of Parkin degradation, via the overexpression of nucleus accumbens 1 (NAC1), on cell viability. It was found that NAC1 and Parkin are co-localized within the cell and interact with one another, leading to a decrease in Parkin levels. Moreover, NAC1 down-regulates Parkin by presenting it for ubiquitin-dependent proteasome degradation, which causes a decrease in proteasomal activity in neuronal cells. Consequently, this decrease in proteasomal activity leads to an increase in the cells' susceptibility to proteasome inhibition-induced toxicity. It was also found that Parkin and NAC1 are key proteins found to be present mainly in the cytoplasm and are co-localized in neurons of Parkinson's disease patients. Interestingly, mutation in the POZ/BTB domain (Q23L) of NAC1 disrupts the co-localization and interaction of NAC1 with Parkin and it further abrogates the proteasome inhibition-induced toxicity. We further observed that co-transfection of the mutant form of NAC1 with Parkin reversed the proteasome activity and 20S proteasome protein levels. These results indicate a novel interaction between NAC1 and Parkin that leads to neuronal cell death, a main characteristic in Parkinson's disease.
Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: Korutla@mail.med.upenn.edu.
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Korutla
Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Furlong
Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Philadelphia Veterans Administration Medical Center (VAMC), Philadelphia, PA 19104, USA.
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Mackler
D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000473:pathology; D002461:Cell Line, Transformed; D002490:Central Nervous System / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D010300:Parkinson Disease / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C484605:Nacc1 protein, mouse; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide; 4′,6-diamidino-2-phenylindole; DAPI; GAPDH; GST; MTT; NAC; PBS; PCR; PD; Parkinson’s disease; SDS–PAGE; UPS; aggregates; co-immunoprecipitation; co-localization; degradation; down-regulation; glutathione S-transferase; glyceraldehyde 3-phosphate dehydrogenase; nucleus accumbens; phosphate-buffered saline; polymerase chain reaction; proteasome; sodium dodecyl sulfate–polyacrylamide gel electrophoresis; ubiquitin–proteasome system