New Approaches for Parkinson's Disease Treatment

Abstract

1. Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. 2. IDUNA (RNF146) is an E3 ubiquitin ligase that specifically recognizes and polyubiquitinates poly (ADP-ribose) (PAR)-conjugated substrates for proteasomal degradation. IDUNA induction has been shown to be neuroprotective against PAR polymerase-1 (PARP1)-induced cell death during stroke. High-throughput screen using a luciferase construct harboring the promoter identified Hydrocortisione and liquiritigenin as parkin and IDUNA inducer, respectively. This treatment in mice increased brain parkin or IDUNA levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway, and liquiritigenin could mediate IDUNA induction via estrogen receptor activation. The identification of inducer of parkin or IDUNA and mechanism might be a potential therapeutic or preventive strategy for Parkinson’s disease.