Mutations in the gene encoding the protein parkin cause an inherited form of Parkinson's disease (PD). Parkin plays a neuroprotective role in response to stresses that affect the ability of neurons to produce energy (ATP) in mitochondria (powerhouses of the cell). Parkin also regulates protein recycling in the cell. To exert its effects, parkin must be activated. By studying pre-clinical models of PD with different forms of parkin, we will clarify its role in mitochondrial function and in the regulation of mitochondrial protein expression.
We hypothesize that loss of parkin will impair the ability of mitochondria in nerve terminals (sites where electrical signals are sent to other neurons) to make energy and that active parkin will enhance the ability of mitochondria in nerve terminals to make energy.
This project will characterize changes in mitochondrial function, number and protein content in pre-clinical PD models that either have normal parkin, do not have parkin or express active parkin, and will then examine nerve terminals, which are very important for brain function and highly dependent on mitochondrial energy production. First, we will determine if differences in parkin lead to alterations in mitochondrial function. By using several assays (analytic tests), we will assess the overall quality of the mitochondria and their ability to produce ATP and measure any associated reactive oxygen species production to assess oxidative stress, a cause of neuron dysfunction and death. Second, we will determine the relative number of functional mitochondria present in brain nerve terminals using a DNA sequencing technique. Third, we will examine changes in the composition and recycling of mitochondrial proteins using a technique that measures chemicals in a sample.
Impact on Diagnosis/Treatment of Parkinson's disease:
The mechanisms of parkin neuroprotection remain incompletely characterized but mitochondria are believed to be involved. We will analyze mitochondrial function and protein expression changes in pre-clinical PD models with different forms of parkin to advance our knowledge of parkin-mediated mitochondrial alterations and reveal the utility of parkin as a target for PD therapeutics.
Next Steps for Development:
If activated parkin is beneficial for mitochondrial function, the next step would be finding a way to enhance parkin activity or mimic the effects of parkin activation on mitochondria.