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

Abstract

Mutations in the <i>PARK2</i> gene are associated with early onset Parkinsonism. The <i>Park2</i> ^<i>-/-</i> 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 <i>Park2</i> ^<i>-/-</i> mouse, suggesting a compensatory mechanism during development. Here we generated the <i>Park2</i> ^<i>-/-</i> <i>Mcl-1</i> ^<i>+/-</i> mouse and show that by reducing <i>Mcl-1</i> gene dosage by 50%, the <i>Park2</i> ^<i>-/-</i> 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.