In vitro and in vivo rescue of dopaminergic neurons in Parkinson's disease models after Parkin gene therapy.

Young-onset Parkinson's disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in Parkin (PRKN). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of PRKN-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9 vectors with different promoters were engineered to deliver PRKN cDNA with efficient human Parkin (hParkin) expression in dopaminergic (DA) neurons as shown in PRKN-null human induced pluripotent stem cell (iPSC) derived DA neurons. Further, we show that AAV9-PRKN treatment can protect nigral DA neurons in two mouse PD models, the 6-hydroxydopamine (6-OHDA)-lesion and the α-synuclein (α-Syn) pre-formed fibrils (PFFs)-lesion model. In summary, AAV9-PRKN gene therapy demonstrates neuroprotective properties and may represent a promising approach for PRKN-PD, with potential broader applications in idiopathic PD and other neurodegenerative diseases.