NAC1, A POZ/BTB protein interacts with Parkin and may contribute to Parkinson's disease

- NAC1 interacts with Parkin through POZ/BTB domain, down-regulates and is co-localized.
- NAC1-triggered down-regulation of Parkin occurs through the UPS system.
- NAC1 and Parkin aggregates are co-localized in the cytoplasm of PD patient's neurons.
- Mt-POZ/BTB disrupts localization, interaction, and abrogates toxicity.
- Established a direct link between NAC1 and Parkin in PD pathogenesis.

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.