Suppression of Nrdp1 toxicity by Parkin in Drosophila models

Nrdp1 is a RING finger ubiquitin E3 ligase that interacts with Parkin, and promotes the degradation of Parkin, a causative protein for early onset Autosomal Recessive Juvenile Parkinsonism (AR-JP). To investigate if Nrdp1 plays a role in the pathogenesis of Parkinson’s disease, we generated transgenic Drosophila that expressed Drosophila Nrdp1 (dNrdp1) and dNrdp1D56V, an aspartic acid to valine mutant at residue 56 that disrupts its ring finger domain, resulting in impaired capacity to degrade its substrate ErbB3. Our data show that a pan-neuronal expression of transgenic dNrdp1 but not dNrdp1D56V mutant leads to the loss of dopaminergic neurons in brains, resulting in reduction of dopamine production. These flies also manifested decreased flight ability. Co-expression of human Parkin (hParkin) provides protection against toxicity induced by over-expression of dNrdp1, reversing the effects of dNrdp1 on death of dopaminergic neurons, reduction of dopamine production, and decreased flight ability. Taken together, we conclude that Nrdp1 plays a role in neurodegeneration and could be potentially targeted as a therapeutic strategy for Parkinson’s disease.

► We generated Drosophila models that overexpress wild type and mutant Nrdp1.
► Nrdp1 leads to the loss of dopaminergic neurons and reduced dopamine production.
► Nrdp1 causes PD like phenotypes.
► Human Parkin provides protection against Nrdp1 overexpression.