# Dissect the mechanisms of selective regional vulnerability in Lewy Body Dementias via comparative snRNA-seq analysis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $720,071

## Abstract

Project Summary
Lewy body diseases (LBDs) are highly heterogeneous neurodegenerative disorders including Parkinson's
disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). LBDs are
characterized by the abnormal aggregation of the protein α-synuclein in neuronal cell bodies (Lewy Body) and
neurites which are currently considered to be the common cause of the diseases. Lewy Body deposition starts
in the caudal brainstem of PD but in the neocortex of DLB cases. The regional differences of initial α-synuclein
deposition correlate with neuronal loss in the corresponding regions - dopamine neurons in the substantia nigra
(SN) and neurons of unknown identity in the neocortex, and the unique clinical manifestations with a predominant
motor symptom in PD whereas early dementia in DLB. Why some particular neurons and brain regions are
affected at the disease onset, whereas the neighboring cells and regions not? This is a fundamental question in
the field of neurodegenerative diseases that this proposal will address via novel genomics technologies and
bioinformatics tools. In an initial pilot study, using single nucleus RNA-sequencing (snRNA-seq) analyses, we
identified a novel disease-associated astrocyte (DAA) subpopulation and demonstrated that DAA contributed to
increased inflammation, amyloid pathology, and neurodegenerative disease pathogenesis whereas
parenchymal astrocytes had compromised functionality in both AD and PD brains. Additionally, we identified
three microglia subpopulations that were similar to but with marker gene expression profiles distinct from the
conventional resting (M0), M1, and M2 activated microglia. We observed deficient microglia functionality shared
across all microglia subpopulations and uniquely up-regulated inflammatory pathways in PD suggesting common
and PD-specific mechanisms of neurodegeneration. These data provide us with an exclusive opportunity to
analyze the relationships between these glia subpopulations and selective regional and neuronal vulnerability in
different diseases. In Aim 1, we will identify vulnerable neuronal types in the frontal cortex (FC) and SN of patients
with PD, PDD, and DLB. In Aim 2, we will test the hypothesis that astrocyte/microglia dysfunction underlies the
mechanism of the selective regional vulnerability of LBD. In Aim 3, we will test the hypothesis that dysregulated
interactions between neurons and astrocytes/microglia underlie the mechanism of the selective neuronal
vulnerability of LBD. Our study will provide deep insights into the molecular mechanisms of selective neuronal
and regional vulnerability in LBDs. Besides, our study will provide molecular biomarkers and tools for neuron
cell-type-specific protection and targeted astrocyte/microglia subpopulation isolation and manipulation.
Furthermore, our study will provide molecular biomarkers for distinguishing PD, PDD, and DLB, which is very
important but a considerable challenge today.

## Key facts

- **NIH application ID:** 10843793
- **Project number:** 5R01NS123571-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jinbin Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $720,071
- **Award type:** 5
- **Project period:** 2021-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843793

## Citation

> US National Institutes of Health, RePORTER application 10843793, Dissect the mechanisms of selective regional vulnerability in Lewy Body Dementias via comparative snRNA-seq analysis (5R01NS123571-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10843793. Licensed CC0.

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