# Defining immune cell heterogeneity in human ALS and mouse model of the disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $450,923

## Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease that is associated with features of
neuroinflammation. Although mounting evidence supports the notion that neuroinflammation may play an active
role in ALS pathogenesis, anti-inflammatory therapies have to provide either no or minimal disease-modifying
effect in ALS. Herein, we hypothesize that since immune cells exhibit a phenotypic heterogeneity, effective
immune response-modifying therapy for ALS requires the targeting of specific components of neuroinflammation
rather than broadly inhibiting its signaling. The rationale for this research is that, once the genomic signatures
of immune cells in the central nervous system (CNS) and the peripheral nervous system (PNS) of ALS are
known, meaningful biomarkers can be identified and innovative therapeutic strategies can be devised. Thus,
the following three aims are proposed. To define the heterogeneity of the immune cell response within the CNS,
in AIM 1, we will perform single-cell RNA-sequencing (scRNASeq) using freshly extracted immune cells from
spinal cord (ALS susceptible region) and hippocampus (ALS resistant region) of patients with ALS as well as of
the extensively used and validated transgenic (Tg) mutant SOD1 (mutSOD1) mouse model of ALS, from pre-
symptomatic to end-stage paralysis. We will then utilize this large-scale multivariable dataset computationally
to construct an integrated CNS immune cell response signature associated with MN degeneration. Since motor
axon degeneration is a critical feature of ALS pathology and takes place outside of the CNS, in AIM 2, we will
perform a phenotypical analysis of peripheral nerve infiltrating adaptive and innate immune cells by scRNASeq
in sciatic nerves from both ALS patients and Tg mutSOD1 mice using the same analytic pipeline as in AIM 1.
We will then computationally construct a bi-compartmental model that integrates the CNS and PNS immune cell
information to generate a neuroinflammatory signature of ALS. Lastly, since subregions of the spinal cord
degenerate unevenly in ALS, we will use the integrated, neuroinflammatory signatures generates in AIM 1 & 2
to: (i) interrogate an existing, comprehensive spatial transcriptome database from both ALS patients and Tg
mutSOD1 mice, and by immunofluorescence and confocal microscopy (ii) localize the different spinal cord
immune cell subpopulations in the respective tissue. Successful completion of the proposed investigations will
establish heterogeneity of the immune cell phenotype in ALS in both the PNS and CNS in response to
neurodegeneration. These findings will have an important positive impact in that they will provide opportunities
for novel pathogenic hypothesis, for identification of biomarkers and for therapeutic interventions in ALS and
related disorders.

## Key facts

- **NIH application ID:** 10160979
- **Project number:** 5R01NS117583-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** SERGE E PRZEDBORSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,923
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160979

## Citation

> US National Institutes of Health, RePORTER application 10160979, Defining immune cell heterogeneity in human ALS and mouse model of the disease (5R01NS117583-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10160979. Licensed CC0.

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