rAAV Fbxo7 gene therapy rescues the progressive nigrostriatal pathology in a mouse model of juvenile parkinsonism

Abstract Mutations in the PARK15/FBXO7 gene cause an early-onset parkinsonian syndrome. A mouse with conditional knockout of Fbxo7 in dopaminergic neurons models key features of this pathology, exhibiting a progressive loss of striatal tyrosine hydroxylase (TH)-positive terminals that precedes cell death. This gradual decline in a mammalian model provided an opportunity to test the capacity of Fbxo7 to act as a therapeutic agent and define a treatment window for gene replacement. Using a recombinant adeno-associated virus (rAAV), we delivered Fbxo7 to test its capacity to prevent (delivery prior to deficit onset) and rescue (delivery after nigrostriatal phenotypes were evident) dopaminergic markers. Remarkably, Fbxo7 re-expression rescued DAT and TH-immunoreactivity in the striatum and nucleus accumbens before and after the onset of the loss of TH + staining. These data establish that Fbxo7-dependent neurodegeneration is not an irreversible process, highlighting its regulated pathways as promising potential targets for developing therapies that will not only slow disease progression, but also ameliorate dopaminergic terminal deficits and potentially restore function.