Reducing Mcl-1 gene dosage induces dopaminergic neuronal loss and motor impairments in Park2 knockout mice

Mutations in the PARK2 gene are associated with early onset Parkinsonism. The Park2 (-/-) mouse, however, does not exhibit neurodegeneration or other Parkinson's disease (PD) phenotypes. Previously, we discovered that translation of Mcl-1, a pro-survival factor, is upregulated in the Park2 (-/-) mouse, suggesting a compensatory mechanism during development. Here we generated the Park2 (-/-) Mcl-1 (+/-) mouse and show that by reducing Mcl-1 gene dosage by 50%, the Park2 (-/-) genotype is sensitized, conferring both dopaminergic neuron loss and motor impairments. We propose that this murine model could be a useful tool for dissecting PD etiology and developing treatment strategies against this neurodegenerative disease.