The PARK2 gene encodes the Parkin protein. It is one of three genes that protect from young-onset Parkinson disease (PD); in Parkin's absence, symptoms and signs usually begin before the age of forty. Despite the gene's discovery in 1998 by Kitada et al., few Parkin-specific antibodies exist. The antibodies available do not readily detect specific, modified forms of Parkin and higher-order variants that are found in the human brain. The lack of variant-specific tools has limited progress and understanding of Parkin's functions in the human brain in both healthy and diseased states.
We hypothesize that the production of renewable, monoclonal antibodies (immune proteins) to specific forms of Parkin, which we have identified in the human brain, will provide a better understanding of its normal and disease-associated processing. These studies should also shed light on how normal Parkin protects dopamine-producing cells in the brain.
We will generate new monoclonal antibodies to three specific isoforms of Parkin protein: a reduced form that carries zinc ions and insoluble, oxidized and dopamine-modified variants. Antibodies will be validated using both human brain specimens (from young, aged healthy participants and participants with PD) and tissues from pre-clinical models carrying mutant genes linked to young-onset Parkinson's. In doing so, we will gain important insight into the normal age- and disease-associated metabolism of Parkin , which will further inform preclinical as well as clinical research.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Parkin-specific antibodies will enable us to study its biology in normal and PD tissues and fluids, thus advancing discovery. Success will likely facilitate the future development of urgently needed therapies for PD.
Next Steps for Development:
The successful generation, initial validation and commercial distribution of renewable antibodies for specific Parkin proteins will enable new discoveries and advance research. Future steps include the development of sensitive Parkin analyses for measuring endogenous (within the body) Parkin in cells, tissues and bodily fluids.