Study Rationale:
Geneticists have made great progress in identifying gene mutations that either cause Parkinson’s or increase disease risk. The critical next step is to determine how some of these mutations perturb the function of brain cells involved in Parkinson’s disease. By advancing knowledge of these processes, our research will help to identify new opportunities for reversing the vulnerabilities that cause the disease.
Hypothesis:
We hypothesize that the functions of multiple Parkinson’s disease genes converge on common biochemical pathways involving endocytic organelles and/or mitochondria within vulnerable cell types.
Study Design:
We will use a comprehensive cell biology tool kit including cutting-edge biochemistry, structural biology, microscopy at different scales, and genome editing tools to elucidate the function of selected Parkinson’s disease genes and the effects produced by their dysfunction both in cellular models in vitro and in mouse and rat models. By defining the molecular and cellular networks in which the products of these genes operate, we hope to identify strategies for reversing the cellular vulnerabilities that cause Parkinson’s disease or increase disease risk.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Similar to assembling the pieces of a puzzle, the project has the potential to reveal interconnections between the functions of distinct Parkinson’s disease genes, thus helping to build an understanding of Parkinson’s disease cell biology. This is a critical step toward the development of therapeutic strategies to make neurons resistant to the dysfunctions that cause Parkinson’s disease.
Next Steps for Development:
The successful completion of our research plan is expected to lead to the identification of druggable cellular processes that oppose the biochemical defects that increase Parkinson’s disease risk. The next logical next step toward clinical application of our research would be the development of drugs that engage these targets.