# A transcriptomic atlas of immune cells in a model of synucleinopathy

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $324,000

## Abstract

Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease with dementia (PDD) and
dementia with Lewy bodies (DLB) have no cure, but all three share signs of α-synuclein (α-syn) pathology and
of neuroinflammation. Although mounting evidence supports the notion that the immune cell response to
neurodegeneration plays an active role in the pathogenesis of the above disorders, anti-inflammatory therapies
have failed, thus far, to provide any beneficial effects in neurodegenerative diseases. We hypothesize that since
immune cells exhibit a phenotypic heterogeneity, effective immune response-modifying therapy for
neurodegenerative diseases requires the targeting of specific components of neuroinflammation rather than the
broad inhibition of its signaling. The rationale for this project is that, once the regional and temporal genomic
signatures of immune cells both inside and outside of the central nervous system (CNS) of animal models of
synucleinopathies are known, meaningful biomarkers can be identified and innovative therapeutic strategies can
be devised for PDD, DLB and even perhaps AD. Thus, the following two aims are proposed. To define the
heterogeneity of the immune cell response to α-syn pathology within the CNS, in AIM 1, we will define brain
immune cell subpopulations in transgenic (Tg) mThy1-α-syn mouse line 61 (a recognized model of
synucleinopathies) by droplet-based single-cell RNA-sequencing (scRNASeq) using freshly extracted immune
cells from different brain regions at time points ranging from 2 (no/minimal neuroinflammation) to 14 months
(overt neuroinflammation); non-Tg littermates will be used as controls. Using computational techniques adapted
to low-depth single-cell RNA-seq data, we will identify transcriptomic subtypes of immune cells from the different
mouse brain regions; this includes estimates of cluster robustness, characterization of cell type-specific genes,
and identification of marker genes. In AIM1, we will also validate the single-cell data by probing for sets of newly-
defined and existing marker genes in situ. Since α-syn pathology also takes place outside of the CNS, in AIM 2,
we will define the phenotypic diversity of the systemic immune cell response to α-syn pathology in blood, spleen
and lymph nodes from Tg Line 61 (and non-Tg littermates) at the same selected time points as in AIM 1, and will
be subjected to the same scRNA-seq procedure and cell type analyses. We will then develop novel bi-
compartmental models to relate changes in CNS and peripheral immune system cells, with the goal of identifying
putative interactions between these two sets of cells in synucleinopathies. Successful completion of the
proposed investigations will establish an atlas of immune cell phenotype heterogeneity in synucleinopathies and
shed light into the cross talk between immune cells localized inside and outside of the CNS in response to α-syn
pathology. These findings will have an important positive impact...

## Key facts

- **NIH application ID:** 9986602
- **Project number:** 5R21AG064596-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** SERGE E PRZEDBORSKI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986602

## Citation

> US National Institutes of Health, RePORTER application 9986602, A transcriptomic atlas of immune cells in a model of synucleinopathy (5R21AG064596-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986602. Licensed CC0.

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