A Role of Protein Parkin in Innate Immunity

Study Rationale:
There is growing evidence that some genes associated with Parkinson's disease (PD) also play a role in immunity. Changes in PRKN -- a gene that directs the production of protein parkin -- can increase the risk of infection with intracellular bacteria, which has been confirmed in pre-clinical models lacking parkin. In addition, inducing inflammation in these models caused selective degeneration of dopaminergic neurons, dopamine-producing brain cells involved in Parkinson's. Our own studies highlighted the role of parkin in the regulation of two cellular processes involved in innate immunity -- a type of immune response -- with different outcomes in neurons and immune cells.

Hypothesis:
We hypothesize that parkin regulates the innate immune response by interacting with proteins simultaneously involved in several immune processes (pathways). We propose that this activity is linked to the neuroprotective function of parkin, which is lost in Parkinson's disease.

Study Design:
The involvement of parkin in inflammatory pathways will be studied in pre-clinical models of Parkinson's and in biosamples from people with mutations in the PRKN gene. We will compare the effect of parkin on immune and nerve cells. Guided by our preliminary results, our study will focus on the inflammasome -- an assembly of several proteins that triggers inflammation -- and on a key immune pathway controlled by protein NF-κB. Moreover, we will investigate the role of parkin in fighting intracellular bacteria and determine whether this process helps eliminate potentially harmful protein clumps in neurons.

Impact on Diagnosis/Treatment of Parkinson's disease:
We have already identified proteins that control the immune pathways of interest. Since the identified proteins function as enzymes, speeding or slowing chemical reactions inside the cell, it is possible to change their activity with drugs.

Next Steps for Development:
If the identified proteins can be confirmed in this study, we would consider searching for drugs that change their activity. The identified proteins could also be evaluated as potential biomarkers (objective measures) of Parkinson's disease.

Additional Support:
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity and the Stop Parkinson Walk as a lead supporter providing funding for this phase of the project.