Biomarker Discovery and Validation in Parkinson’s Disease (U01)
Summary
PD pathogenesis is mediated by a complex and interconnected cascade of protein and cellular interactions within the substantia nigra (SN) and other areas of the brain that ultimately induce Lewy body formation, neuronal cell dysfunction, and cell death. However, the metabolic and pathologic changes that manifest during PD onset and progression have not yet been clearly defined. Thus, PD is commonly diagnosed based on clinical criteria of cardinal motor indicators of the disease, patient response to drug treatment and medical history. Because diagnosis based on clinical features alone sometimes results in misdiagnosis, more robust, reliable and reproducible diagnosis methods are required. Further, the absence of definitive diagnostic testing for PD continues to hinder early patient access to disease modifying treatments. The most sensitive method to date developed is based on neuroimaging techniques, which is still limited by high cost, accessibility and overlap with other atypical parkinsonian disorders. As an alternative diagnostic approach, biomarker discovery from cerebral spinal fluid (CSF), which is directly influenced by biochemical processes in the brain, offers an attractive opportunity for biomarker discovery. The correlation of the candidates identified thus far with PD is not strong and is also complicated by a lack of reproducibility by other independent studies. Using state-of-the-art mass spectrometry to define the proteomic signature of PD provides a significant opportunity for successful biomarker discovery. In addition to defining the PD proteome within the CSF, this proposal will also focus on harnessing the power of proteomic alterations that occur in substantia nigra of patients with confirmed PD to provide a list of most likely candidates that will be tested by targeted parallel reaction monitoring (PRM)-based mass spectrometry approaches. Using this unique approach, we hope to define a set of proteins whose performance can be finally validated using CSF from Parkinson’s Disease Biomarker Program (PDBP).