# Understanding the Role of Blood-Based Parkinson's Disease Biomarkers in Neurodegeneration

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $32,737

## Abstract

Project Summary/Abstract
Parkinson’s disease (PD) is the 2nd most common neurodegenerative disorder in the world and is associated
with intracellular α-synuclein (α-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 α-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 α-syn-mediated toxicity, GPNMB will be manipulated in mouse primary cortical neurons and
human iPSC-derived neurons. Cells will then be treated with α-syn pre-formed fibrils (capable of seeding Lewy
Body-like pathology in vitro) and assessed for readouts of 1) α-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.

## Key facts

- **NIH application ID:** 9991184
- **Project number:** 1F31NS113481-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Maria Eugenia Diaz Ortiz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,737
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991184

## Citation

> US National Institutes of Health, RePORTER application 9991184, Understanding the Role of Blood-Based Parkinson's Disease Biomarkers in Neurodegeneration (1F31NS113481-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9991184. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*