Parkinson?s disease (PD) is the 2nd most common neurodegenerative disorder in the world and is associated with intracellular ?-synuclein (?-syn) inclusions and progressive neuronal loss. There are currently no disease modifying therapies for PD due to a poor understanding of disease pathogenesis and lack of clearly intervenable targets. Despite a rise in genome-wide association studies (GWAS), there is an unmet need in the PD field for (1) generation of causal leads for understanding PD progression and (2) mechanistic follow-up of these leads to elucidate their role in neurodegeneration. To this end, the Chen-Plotkin lab performed an unbiased proteomic screen of >1,000 plasma proteins in >450 patients and controls across 3 clinical sites. This study resulted in 140 candidate plasma biomarkers that associated with PD in the discovery cohort. Furthermore, low levels of plasma Glycoprotein non-metastatic protein B (GPNMB) ? a locus previously associated with PD by GWAS ? predicted faster rate of subsequent cognitive decline. Thus, this proposal aims to (1) identify which of the leads generated through this unbiased screen are causally linked to PD and to (2) understand how altered levels of GPNMB contribute to neurodegeneration in PD.
Aim 1 will test the hypothesis that causal leads can be identified using mendelian randomization (MR), a statistical technique using genetic variants as instruments to deduce causality. MR will be applied to leads identified previously by performing a protein quantitative trait loci (pQTL) study and incorporating existing GWAS data for causal inference.
Aim 2 will test the hypothesis that low levels of GPNMB contribute to neurodegeneration by increasing neuronal susceptibility to ?-syn-induced toxicity. To validate existing GPNMB QTL and biomarker signatures in a larger cohort, GPNMB expression in plasma and CSF of 196 PD patients and 98 controls will be quantified by ELISA. Second, to test the effect of GPNMB levels on ?-syn-mediated toxicity, GPNMB will be manipulated in mouse primary cortical neurons and human iPSC-derived neurons. Cells will then be treated with ?-syn pre-formed fibrils (capable of seeding Lewy Body-like pathology in vitro) and assessed for readouts of 1) ?-syn seeding and aggregation, 2) autophagosomal- lysosomal function, and 3) neuronal health. This project will not only provide useful insight into PD pathogenesis, but will also allow the applicant to train in both computational and cellular/molecular biology approaches through the performance of experiments, attendance at seminars, courses, and scientific meetings, and formal guidance from an experienced mentorship team. Furthermore, as a biobank housing thousands of patient samples and an affiliated lab of the Penn Center for Neurodegenerative Diseases, the Chen-Plotkin lab at the University of Pennsylvania is particularly well suited to support the applicant in completion of this project.
Parkinson?s disease (PD) is the 2nd most common neurodegenerative disorder, accounting for ~5 million cases worldwide, and there are currently no disease modifying therapies for PD. Recent large scale genomic and proteomic screens (including our own) have generated leads for understanding and potentially intervening in PD progression, but elucidating their involvement in the neurodegenerative cascade has lagged behind discovery. Therefore, we aim to establish causal links between our biomarker leads and neurodegeneration in PD through computational approaches and bench-based functional characterization, in the hopes of identifying potential therapeutic targets.
