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.
Susanna Ekholm-Reed et al. develop a Parkinson mouse model by reducing Mcl-1 gene dosage by half, which leads to dopaminergic cell loss and motor impairments in Park2 knockout mice that otherwise do not exhibit any of the hallmark phenotypes associated with Parkinson’s disease.