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Neuropathic pain in a Fabry disease rat model
James J. Miller, … , Cheryl L. Stucky, Nancy M. Dahms
James J. Miller, … , Cheryl L. Stucky, Nancy M. Dahms
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e99171. https://doi.org/10.1172/jci.insight.99171.
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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 4

Glycosphingolipid (GSL) storage in Fabry rat brain and dorsal root ganglia.

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Glycosphingolipid (GSL) storage in Fabry rat brain and dorsal root gangl...
(A) Extracted GSLs from 13-week-old male rat brains (3 WT, 3 KO) were analyzed by TLC using a solvent system of chloroform/methanol/water (60:40:10, v/v/v). (B) GSLs from the 3 WT and 3 KO male brains in A were quantified by nanospray ionization–mass spectrometry (NSI-MS) (note the log scale on the y axis). (C) GSLs were extracted from 13-week-old dorsal root ganglia (DRG) and were analyzed by TLC using a solvent system of chloroform/methanol/water (60:35:8, v/v/v). (D) NSI-MS was used to quantify GSLs from WT and KO DRG (note the log scale on the y axis). WT DRG quantification consists of 2 WT males and 1 WT female, and KO DRG quantification consists of 2 KO males and 1 KO female. Gb3 species are outlined with the red box in A and C. In B and D, mean ± SEM are shown and GSL means from WT and KO samples are compared using unpaired, 2-tailed t tests. If a significant difference in mean is detected, the fold increase in KO GSL is shown above in red. GSL species detected in KO, but not WT, DRG are highlighted with light blue boxes. CMH, ceramide monohexoside; CDH, ceramide dihexoside; Gb3, globotriaosylceramide; Gb4, globotetraosylceramide; lyso-Gb3, globotriaosylsphingosine; GQ1, tetrasialoganglioside GQ1; GT1, trisialoganglioside GT1; GD1, disialoganglioside GD1; GD3, disialoganglioside GD3; GM1, monosialoganglioside GM1; GM2, monosialoganglioside GM2; GM3, monosialoganglioside GM3; Gal, galactose; HET, heterozygous. *P < 0.05, **P < 0.01.