Objective/Rationale:
Parkinson’s disease is, at least in part, a disease caused by misfolding and aggregation of the protein alpha-synuclein. Boosting the natural degradation machinery of diseased neurons should thus reduce accumulation of toxic misfolded proteins, and improve the health of diseased neurons. This project will pharmacologically induce pathways of protein degradation in rat brain, and look for corresponding protein changes in cerebrospinal fluid (CSF). Identification of protein biomarkers of drug-induced protein degradation in CSF would be important for testing therapeutics utilizing this mechanism in human Parkinson’s disease patients.
Project Description:
Pre-clinical models will be treated with drugs known to induce misfolded protein clearance in cells and animals. CSF of treated models will be drawn, and subjected to detailed proteomic analysis. We will use a sensitive technique with the ability to analyze changes in the concentrations of hundreds of proteins, and will screen for proteins whose abundance increases or decreases in the CSF of drug-treated models. Proteins that change will be unequivocally identified by mass spectrometric analysis. It is anticipated that a signature of drug-induced protein clearance will be identified in CSF. The unbiased nature of the experiment will facilitate the discovery of these novel signatures.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
One of the major new areas of interest in Parkinson’s disease research is in attempting to stimulate the natural processes of toxic protein degradation. Developing clinical biomarkers which can measure protein clearance will be important in measuring patient response to drug treatments in clinical trials, and will increase the likelihood of the successful development of new medicines for treating Parkinson’s disease.
Anticipated Outcome:
This project aims to identify clinically useful biomarkers of a novel therapeutic approach to treating Parkinson’s disease, i.e. the stimulation of toxic protein aggregate breakdown in neurons. Such biomarkers will be critical in guiding the clinical testing of new therapeutics based on this general approach. We anticipate identifying a number of candidate biomarkers of drug activity in the brain and CSF which will be further analyzed and validated in preparation for utilization in clinical trials.
Final Outcome
This project examined the pharmacologically induced stimulation of protein degradation pathways in the rodent brain, and corresponding protein biomarker changes in cerebrospinal fluid (CSF). Pre-clinical models were treated with drugs known to induce misfolded protein clearance in pre-clinical models. CSF of treated models was successfully subjected to detailed proteomic analysis and screened for proteins whose abundance increased or decreased compared to non-treated models. Using this approach, the researchers identified proteins that changed upon drug treatment, and which could represent a novel biomarker signature of increased protein turnover in brain. As new drug treatments come to the clinic to be tested in PD patients, especially those designed to stimulate the natural processes of toxic protein degradation, it will be crucial to have available clinical biomarkers which can act as surrogate markers of patient response. We plan to further analyze and validate these markers in preparation for their use in clinical trials.