# Pain Mechanisms in Fabry Disease

> **NIH NIH R37** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $769,483

## Abstract

Project Summary
The central goal of this project is to identify the cellular mechanisms that underlie the mechanical
hypersensitivity and pain in Fabry Disease (FD), and thereby identify novel targets for improved pain treatment.
FD is the most common lysosomal storage disease. It results from a deficiency of the lysosomal enzyme α-
galactosidase A (α-Gal A) that leads to the accumulation of glycosphingolipids within the lysosomes of cells
including dorsal root ganglia (DRG) neurons. Small fiber neuropathy is a hallmark of FD. Neuropathic-like pain
begins around age 5, worsens with age, and affects 60-80% of all (male and female) patients. The pain is
described as episodic “pain crises” triggered by fever, exercise, fatigue or stress, and chronic “permanent
pain.” We created a transgenic rat model of FD using CRISPR/Cas9 to delete the gene encoding α-Gal A.
Fabry rats closely recapitulate many phenotypes observed in patients, including elevated serum levels of α-
galactosyl glycosphingolipids, spontaneous and mechanically-evoked pain behavior, pronounced lipid
inclusions and aberrant accumulation of α-galactosyl glycosphingolipids in small-diameter DRG neurons and
severe hearing loss. Sensory neurons somata from Fabry rats have sensitized rapidly adapting mechanical
currents and sensitized responses to mustard oil, suggesting that Piezo2 and TRPA1 channel activities may be
enhanced. Inhibition of TRPA1 alleviates the behavioral mechanical hypersensitivity in FD. Afferent fibers also
show clear spontaneous activity, which may underlie the ongoing pain. The Scientific Premise of this
proposal is that DRG sensory neurons in FD are dysfunctional and that the glycosphingolipids elevated in FD
sensitize Piezo2 and TRPA1 channels in sensory neurons, resulting in the mechanical hypersensitivity and
ongoing pain. This proposal will define the mechanisms that mediate Fabry disease pain in a top-down
approach through Aims that 1) define the stimulus evoked, ongoing, and crisis-evoked pain behavior over time
in male and female Fabry rats, 2) determine if the DRG is a key site for the generation and maintenance of
mechanical and ongoing pain, and 3) interrogate whether Piezo2 and/or TRPA1 ion channels mediate the
mechanical sensitization observed in the Fabry rat. In addition to identifying pain mechanisms that are FD-
specific, these studies will have a broader impact by identifying mechanisms that could advance the
understanding of mechanisms that underlie tactile allodynia and spontaneous pain in other types of
neuropathic disorders and uncover novel roles for lipids in mechanotransduction mechanisms in
somatosensory systems.

## Key facts

- **NIH application ID:** 9929049
- **Project number:** 5R37NS108278-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Cheryl Louise Stucky
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $769,483
- **Award type:** 5
- **Project period:** 2019-05-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929049

## Citation

> US National Institutes of Health, RePORTER application 9929049, Pain Mechanisms in Fabry Disease (5R37NS108278-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9929049. Licensed CC0.

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