Insights into human disease mechanisms using Drosophila: Cdk8 regulates a Parkinson’s Disease Model

Cyclin-dependent kinase 8 (Cdk8) acts with the Mediator complex to regulate RNA polymerase II-meditated transcription. While its role in transcription has been well established in different model organisms, there is limited information about its potential Mediator-independent functions. We find that when Cdk8 is knocked down ubiquitously in Drosophila, it causes defects in flight and climbing ability, as well as reduced lifespan. These phenotypes are found in flies mutant for either Pink1 (PTEN-induced putative kinase 1) or Parkin in Drosophila models of Parkinson’s Disease. Pink1 and Parkin act in quality control of mitochondria. pink1 loss of function leads to the accumulation of damaged mitochondria. We find that ectopic expression of Cdk8 can significantly rescue pink1 mutant phenotypes, including locomotor impairment and defects in mitochondrial morphology and integrity. Furthermore, we show that Cdk8 and its partner CycC regulate mitochondrial morphology under physiological conditions.