# Project III: Heterogeneity of Outcomes in Synucleinopathies: Insights from Genomics and Proteomics

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $510,328

## Abstract

PROJECT III SUMMARY/ABSTRACT
Heterogeneity of Outcomes in Synucleinopathies: Insights from Genomics and Proteomics
While patients with Lewy body disorders (LBD) share the core feature of deposition of misfolded alpha-synuclein
(aSyn) into neuropathological inclusions, they exhibit pronounced heterogeneity in both initial clinical
phenomenology, as well as in trajectory of cognitive outcomes. The reasons for these differences in
phenomenology among synucleinopathy patients are not well understood, but these differences matter greatly
for quality of life for patients and their families, as well as costs to the healthcare system. The central tenet of
this Project is that host characteristics play an important role in determining which LBD patients manifest with
cognitive impairment at disease onset vs. years into disease vs. decades into disease vs. not at all. The goal of
Project III is to investigate the host characteristics represented by common genetic risk variants (associated
with risk for DLB, PD, and cognitive impairment in the LBD), as well as those host characteristics represented in
protein biomarker signatures, in order to uncover mechanisms that drive cognitive decline in the LBD. We will
do this through three specific aims.
SPECIFIC AIM 1: Assign target genes to loci associated with risk for LBD as well as cognitive decline
within PD. More than 90 loci have been reported to associate with PD risk or DLB risk by GWAS, with additional
loci reported to associate with cognitive decline within PD. The vast majority of these loci are non-coding, and
target genes are unclear. We will assign target genes based on colocalization analyses, comparing our work
with existing reports and confirming expression quantitative trait locus (eQTL) effects in PD brain tissue with
allele-specific expression (ASE) assays.
SPECIFIC AIM 2: Perform causal inference analyses for biomarkers associating with cognitive outcome
in PD. We will perform CSF biomarker screens and investigate biomarker leads emerging from these CSF
screens as well as our previously-performed plasma biomarker screens of thousands of proteins in multiple
cohorts of PD patients. We will evaluate these leads for a causal role in cognitive decline by performing
Mendelian randomization-based causal inference analyses.
SPECIFIC AIM 3: Determine effects of nominated targets on development of aSyn pathology in cortical
iPSC-N. Preliminary data suggest that Aims 1 and 2 will generate 20-40 potential targets for downstream
manipulation in induced pluripotent stem cell-derived neurons (iPSC-N). We will prioritize these leads based on
the strength of both the genomic and proteomic evidence in order to select 5-15 targets. We will use CRISPR-
based techniques to manipulate expression of the selected targets in cortical iPSC-N, in order to determine
effects on uptake of fibrillar aSyn, cell-to-cell transmission of aSyn species, and development of aSyn pathology.

## Key facts

- **NIH application ID:** 10935311
- **Project number:** 1P01AG084497-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ALICE S CHEN-PLOTKIN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $510,328
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935311

## Citation

> US National Institutes of Health, RePORTER application 10935311, Project III: Heterogeneity of Outcomes in Synucleinopathies: Insights from Genomics and Proteomics (1P01AG084497-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10935311. Licensed CC0.

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