Long-term overexpression of human wild-type and T240R mutant Parkin in rat substantia nigra induces progressive dopaminergic neurodegeneration.

Abstract

Mutations in the parkin gene are the most common cause of early-onset autosomal recessive Parkinson disease (PD). The pathogenic mechanisms of how parkin mutations lead to the development of PD are not fully understood. Studies of cell cultures and of Drosophila have suggested a dominant negative effect for the clinical parkin mutant T240R. Conversely, the neuroprotective capacity of parkin has been widely reported; this suggests that the parkin protein may have a potential therapeutic role in PD. Here, we aimed to develop a novel genetic rodent model of PD by overexpression of T240R-parkin and human wild-type parkin as a control in the dopaminergic neurons of adult rats using adeno-associated viral vectors (rAAV2/8). Surprisingly, we found that overexpression not only of T240R-parkin but also of human wild-type parkin induced progressive and dose-dependent dopaminergic cell death in rats, starting from 8 weeks after injection. This degeneration was specific for parkin because similar overexpressionof enhanced green fluorescent protein did not lead to nigral degeneration. Our results warrant caution to the development of therapeutic strategies for PD based on overexpression of parkin or enhancing parkin activity because this might be deleterious for dopaminergic neurons in the long-term.