Molecular mechanism of JNK attenuation by parkin

Abstract

Parkinson's disease (PD) is characterized by the disappearing pigmentation, accumulation of lewy bodies, and the ultimate degeneration of neurons in the substantia nigra pars compacta region of the brain. The most prevalent indication of hereditary PD is a mutation in the PARKIN gene. Parkin facilitates the proteasomal degradation of target proteins through its ubiquitination‐catalyzing activity. The E3 ubiquitin ligase has been further implicated in attenuating the activation of the c‐jun N‐terminal kinase (JNK) pathway, a pro‐apoptotic mitogen‐activated protein kinase (MAPK) signaling cascade, implying neuroprotective characteristics. However, the mechanism whereby parkin regulates the JNK pathway remains obscure. Utilizing in vitro pull‐down assays in tandem with co‐immunoprecipitation methods, we have identified a novel interaction between parkin and apoptosis signal‐regulating kinase (ASK‐1), an upstream kinase in the JNK pathway. This interaction was characterized through co‐overexpression in HEK293T cells, which indicated the parkin‐induced degradation of ASK1. In vitro ubiquitination assays showed an enhanced activation of parkin in the presence of ASK1. Our results suggest the interaction with ASK1 is able to disrupt the intrinsic auto‐inhibition of parkin, enhancing its activation to carry out the ubiquitin‐signaled degradation of ASK1.Support or Funding InformationTennessee Technological University Chemistry Department Student Research Grant