Neuropathic pain in a Fabry disease rat model

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

doi:10.1172/jci.insight.99171

Cited by 54 publications

(107 citation statements)

References 94 publications

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“…Globotriaosylceramide synthase (Gb3S) catalyzes the addition of α-1,4-galactose to lactosylceramide (LacCer), which produces globotriaosylceramide (Gb3), whose deacylated form is LysoGb3. In Fabry disease, accumulation of substrates containing terminal α-galactose: Gb3, LysoGb3, galabiosylceramide (Ga2/Gb2/Gal2Cer) has been reported [20,21]. In turn, galabiosylceramide (Ga2) is a structural isomer of LacCer.…”

Section: Discussionmentioning

confidence: 99%

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

et al. 2020

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Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease-Fabry disease. The connection between MPSs and LysoGb3 has not yet been established. This study included 36-MPS I, 15-MPS II, 25-MPS III, 26-MPS IV, and 14-MPS VI patients who were diagnosed by biochemical and molecular methods and a control group of 250 males and 250 females. The concentration of lysosphingolipids (LysoSLs) was measured in dried blood spots by high pressure liquid chromatography-tandem mass spectrometry. We have demonstrated that LysoGb3 concentration was significantly elevated (p < 0.0001) in untreated MPS I (3.07 + 1.55 ng/mL), MPS II (5.24 + 2.13 ng/mL), and MPS III (6.82 + 3.69 ng/mL) patients, compared to the control group (0.87 + 0.55 ng/mL). LysoGb3 level was normal in MPS VI and MPS IVA (1.26 + 0.39 and 0.99 + 0.38 ng/mL, respectively). Activity of α-galactosidase A (α-Gal A), an enzyme deficient in Fabry disease, was not, however, inhibited by heparan sulfate in vitro, indicating that an increase of LysoGb3 level in MPS I, MPS II, and MPS III is an indirect effect of stored MPSs rather than a direct result of impairment of degradation of this compound by HS. Our findings indicate some association of elevated LysoGb3 concentration with the neuronopathic forms of MPSs. The pathological mechanism of which is still to be studied.

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Section: Discussionmentioning

confidence: 99%

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

et al. 2020

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“…It is of note that acute heat sensitivity is based on three different transient receptor potential channels indicating high redundancy ( Vandewauw et al, 2018 ). A recent study investigating a rat model of FD provided evidence for TRPA1 dependent mechanical but not thermal hypersensitivity in a Fabry rat model without differences in TRPV1 currents in young rats ( Miller et al, 2018 ). In line with these results, current properties of TRPV1 did not differ between young GLA KO and WT mice in our experiments ( Figure 3J ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of small fiber pathology in a mouse model of Fabry disease

Hofmann

Hose

Grießhammer

et al. 2018

eLife

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Fabry disease (FD) is a life-threatening X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Small fiber pathology and pain are major FD symptoms of unknown pathophysiology. α-GAL deficient mice (GLA KO) age-dependently accumulate globotriaosylceramide (Gb3) in dorsal root ganglion (DRG) neurons paralleled by endoplasmic stress and apoptosis as contributors to skin denervation. Old GLA KO mice show increased TRPV1 protein in DRG neurons and heat hypersensitivity upon i.pl. capsaicin. In turn, GLA KO mice are protected from heat and mechanical hypersensitivity in neuropathic and inflammatory pain models based on reduced neuronal Ih and Nav1.7 currents. We show that in vitro α-GAL silencing increases intracellular Gb3 accumulation paralleled by loss of Nav1.7 currents, which is reversed by incubation with agalsidase-α and lucerastat. We provide first evidence of a direct Gb3 effect on neuronal integrity and ion channel function as potential mechanism underlying pain and small fiber pathology in FD.

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“…GSLs were isolated and quantified as previously described (10). In brief, GSLs were extracted and purified from kidney and heart homogenates and were permethylated with 12 C-methyliodide.…”

Section: Gsl Mass Spectrometrymentioning

confidence: 99%

α‐Galactosidase A‐deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease

et al. 2018

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Fabry disease is an X-linked lysosomal storage disease caused by α-galactosidase A (α-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because α-Gal A-deficient mouse models do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry rat model. We found that male Fabry rats weighed significantly less than wild-type (WT) males, whereas female Fabry rats weighed significantly more than WT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealed that inflammation and lipoatrophy may be chief disease mediators in patients. With respect to the kidney and heart, we found that both organs accumulate α-Gal A substrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observed in Fabry rats using echocardiography. We conclude that Fabry rats recapitulate important kidney and heart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.-Miller, J. J., Aoki, K., Mascari, C. A., Beltrame, A. K., Sokumbi, O., North, P. E., Tiemeyer, M., Kriegel, A. J., Dahms, N. M., α-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease.

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Neuropathic pain in a Fabry disease rat model

Cited by 54 publications

References 94 publications

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Characterization of small fiber pathology in a mouse model of Fabry disease

α‐Galactosidase A‐deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease

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