Neuropathic pain in a Fabry disease rat model
James J. Miller, Kazuhiro Aoki, Francie Moehring, Carly A. Murphy, Crystal L. O’Hara, Michael Tiemeyer, Cheryl L. Stucky, Nancy M. Dahms
James J. Miller, Kazuhiro Aoki, Francie Moehring, Carly A. Murphy, Crystal L. O’Hara, Michael Tiemeyer, Cheryl L. Stucky, Nancy M. Dahms
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Research Article Neuroscience

Neuropathic pain in a Fabry disease rat model

Abstract

Fabry disease, the most common lysosomal storage disease, affects multiple organs and results in a shortened life span. This disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. Neuropathic pain is an early and severely debilitating symptom in patients with Fabry disease, but the cellular and molecular mechanisms that cause the pain are unknown. We generated a rat model of Fabry disease, the first nonmouse model to our knowledge. Fabry rats had substantial serum and tissue accumulation of α-galactosyl glycosphingolipids and had pronounced mechanical pain behavior. Additionally, Fabry rat dorsal root ganglia displayed global N-glycan alterations, sensory neurons were laden with inclusions, and sensory neuron somata exhibited prominent sensitization to mechanical force. We found that the cation channel transient receptor potential ankyrin 1 (TRPA1) is sensitized in Fabry rat sensory neurons and that TRPA1 antagonism reversed the behavioral mechanical sensitization. This study points toward TRPA1 as a potentially novel target to treat the pain experienced by patients with Fabry disease.

Authors

James J. Miller, Kazuhiro Aoki, Francie Moehring, Carly A. Murphy, Crystal L. O’Hara, Michael Tiemeyer, Cheryl L. Stucky, Nancy M. Dahms

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Figure 5

Complex and hybrid N-glycans are decreased in Fabry rat dorsal root ganglia (DRG).

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Complex and hybrid N-glycans are decreased in Fabry rat dorsal root gang...
N-glycans were prepared from DRG obtained from males at 13 weeks of age. Full mass spectra from WT (top) and KO (bottom) are shown. Peaks colored magenta report the abundance of the annotated high-mannose glycans. Structural assignments for complex and hybrid N-glycans are based on collision-induced dissociation fragmentation performed in nanospray ionization–tandem mass spectrometry analyses of the released, permethylated glycans. The maltotetraose (Dp4) peak corresponds to a standard permethylated glycan that was added to both samples to give the same final concentration, providing a reference for comparing glycan quantities. The sulfated, disialylated hybrid structure, detected at m/z 1416 (m+Na)2+ and 952 (m+Na)3+ is one of the glycans that exhibits a striking decrease in Fabry rat DRG (Structure 19 in Supplemental Table 1 and Supplemental Figure 3, fragmented in Supplemental Figure 4).