# Protein Arginine Deiminase 2 (PAD2) and Protein Citrullination in ALS

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $487,663

## Abstract

Project Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron
degeneration, muscle weakness, paralysis, and death. The mechanism of motor neuron degeneration is
incompletely understood, and currently, no therapy can arrest or reverse the disease progression. To
understand the disease and open new avenues for therapy, exploring new mechanisms of the disease is
needed. To this end, the Xu and Thompson labs have joined forces to investigate the role of protein
citrullination, which is catalyzed by Protein Arginine Deiminases (PADs), in ALS. Citrullination removes positive
charges from proteins. Therefore, this modification can alter the protein function and its interaction with other
proteins, membranes, and nucleic acids. Mammals have five PADs: PADs 1–4 and PAD6. PAD2 is the
dominant form in the central nervous system (CNS). Previous studies have shown that PAD2 and protein
citrullination are increased in neurodegenerative diseases such as Alzheimer's disease and Prion disease.
However, no studies have linked PADs and protein citrullination with ALS. Furthermore, no studies have
investigated the functional role of PAD2 and protein citrullination in neurodegeneration. To fill these knowledge
gaps, the Xu and Thompson labs have applied their combined expertise in ALS and protein citrullination and
initiated this investigation. Our preliminary studies show unequivocal evidence that PAD2 expression (but not
PAD3, 4) and protein citrullination are spatially and temporally altered in two ALS mouse models, one
expressing mutant SOD1G93A and the other expressing mutant PFN1C71G. While PAD2 expression is increased
in astrocytes, its expression is decreased in neurons during the disease progression. By proteomics, we
identified several hundred citrullinated proteins in the spinal cord. In ALS mice, the early disease stage is
dominated by decreased protein citrullination. In contrast, the late disease stage shows increased citrullination
in one-half of the proteins and decreased citrullination in the other half. Intriguingly, the highly citrullinated
proteins are enriched in the insoluble fractions in the late stage. We propose to further our investigation by
answering the following seven questions: (1) How is protein citrullination altered in ALS? (2) What are the
citrullinated proteins in the spinal cord, and how is citrullination altered in these proteins in ALS? (3) What are
the sites of citrullination on ALS-associated proteins? (4) Is PAD2 responsible for the altered protein
citrullination in ALS? (5) How does protein citrullination impact protein aggregation? (6) How does the
citrullination of ALS-associated targets impact their protein function? (7) How is protein citrullination altered in
human ALS? By answering these questions, we will enter and investigate a hitherto unexplored research area
in ALS, thereby opening a new dimension in understanding the mechanism of neurodegeneration in ALS.
...

## Key facts

- **NIH application ID:** 10399654
- **Project number:** 5R01NS118145-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** ZUOSHANG XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $487,663
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399654

## Citation

> US National Institutes of Health, RePORTER application 10399654, Protein Arginine Deiminase 2 (PAD2) and Protein Citrullination in ALS (5R01NS118145-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10399654. Licensed CC0.

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