Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model

Abstract

Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types. Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types. Fabry disease is an X-linked metabolic disorder that results from deficiency of the lysosomal hydrolase, α-galactosidase A (α-gal A) (1Brady R.O. Gal A.E. Bradley R.M. Martensson E. Warshaw A.L. Laster L. Enzymatic defect in Fabry disease: ceramide trihexosidase deficiency.N. Engl. J. Med. 1967; 276: 1163-1167Crossref PubMed Scopus (789) Google Scholar), which leads to intracellular accumulation of glycosphingolipids (GSLs) with a terminal α-linked galactosyl moiety in various tissues. Known substrates of α-gal A include globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), galabiosylceramide (Gb2), blood groups B and P1 glycolipids, and isoglobotriaosylceramide (iGb3) (2Desnick, R. J., Y. A., Ioannou, and C. M., Eng, . 2001. α-Galactosidase A deficiency: Fabry disease. In The Metabolic and Molecular Bases of Inherited Disease. C. R. Scriver, A. L. Beaudet, W. S. Sly, et al., editors. McGraw-Hill, New York. 3733–3774.Google Scholar, 3Aerts J.M. Groener J.E. Kuiper S. Donker-Koopman W.E. Strijland A. Ottenhoff R. van Roomen C. Mirzaian M. Wijburg F.A. Linthorst G.E. et al.Elevated globotriaosylsphingosine is a hallmark of Fabry disease.Proc. Natl. Acad. Sci. USA. 2008; 105: 2812-2817Crossref PubMed Scopus (468) Google Scholar, 4Boutin M. Menkovic I. Martineau T. Vaillancourt-Lavigueur V. Toupin A. Auray-Blais C. Separation and analysis of lactosylceramide, galabiosylceramide, and globotriaosylceramide by LC-MS/MS in urine of Fabry disease patients.Anal. Chem. 2017; 89: 13382-13390Crossref PubMed Scopus (19) Google Scholar, 5Speak A.O. Salio M. Neville D.C. Fontaine J. Priestman D.A. Platt N. Heare T. Butters T.D. Dwek R.A. Trottein F. et al.Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals.Proc. Natl. Acad. Sci. USA. 2007; 104: 5971-5976Crossref PubMed Scopus (133) Google Scholar). Fabry disease exhibits a variety of clinical manifestations, including stroke, hypertrophic cardiomyopathy, renal insufficiency, and painful small-fiber neuropathy (2Desnick, R. J., Y. A., Ioannou, and C. M., Eng, . 2001. α-Galactosidase A deficiency: Fabry disease. In The Metabolic and Molecular Bases of Inherited Disease. C. R. Scriver, A. L. Beaudet, W. S. Sly, et al., editors. McGraw-Hill, New York. 3733–3774.Google Scholar). Currently, enzyme replacement therapy (ERT) and pharmacological chaperones are the commercially approved treatments for Fabry disease. Other promising approaches, such as substrate reduction therapy and gene therapy are under development (6Ashe K.M. Budman E. Bangari D.S. Siegel C.S. Nietupski J.B. Wang B. Desnick R.J. Scheule R.K. et of enzyme and substrate reduction therapy with a of for Fabry Med. PubMed Scopus Google Scholar, J. A. L. M. M. M. et and for of Fabry 2017; PubMed Scopus Google Scholar, A. S. L. R.O. A. of globotriaosylceramide in Fabry disease by substrate 105: PubMed Scopus Google Scholar). The which accumulated the is Gb3 and lyso-Gb3 are to responsible for the pathogenesis of the is and in Fabry not with and Gb3 levels Linthorst G.E. van Groener J.E. Strijland A. J.M. The Fabry of clinical and Gb3 2007; PubMed Scopus Google Scholar). was to M. A. C. M. T. S. et of lyso-Gb3 as a for with Fabry disease from for Med. PubMed Scopus Google there is no of lyso-Gb3 levels with disease J.M. Groener J.E. Kuiper S. Donker-Koopman W.E. Strijland A. Ottenhoff R. van Roomen C. Mirzaian M. Wijburg F.A. Linthorst G.E. et al.Elevated globotriaosylsphingosine is a hallmark of Fabry disease.Proc. Natl. Acad. Sci. USA. 2008; 105: 2812-2817Crossref PubMed Scopus (468) Google Scholar). In Gb3 and lyso-Gb3 may not for The of lyso-Gb3 not with a in et not a marker for the of enzyme replacement therapy for Fabry with the J. PubMed Scopus Google Scholar). lyso-Gb3 a to to the et not a marker for the of enzyme replacement therapy for Fabry with the J. PubMed Scopus Google Scholar). Fabry for and we found that Fabry cardiac and renal hypertrophy M. S. R. cardiac and renal hypertrophy in Fabry PubMed Scopus Google Scholar). with Fabry increased heart and and cardiac of hypertrophy not and and hypertrophy in Fabry was in to was no of renal M. S. R. cardiac and renal hypertrophy in Fabry PubMed Scopus Google Scholar). Fabry M. R.O. and in the Fabry PubMed Scopus Google Scholar, D.S. K.M. Desnick R.J. C. J. Budman E. J. et A pathology the of Fabry J. PubMed Scopus Google that small-fiber neuropathy in However, due to the of such as cell of fatty acid and the between that is to the of a by using in Gb3 by of Gb3 which is responsible for of Gb3 and in Fabry was with of A. M. T. J. S. A Fabry disease mouse by globotriaosylceramide J. PubMed Scopus Google Scholar). However, that Gb3 is in a cell in the and is by various including cell and I. T. M. E. Y. of for and is by the cell Sci. PubMed Google Scholar, Molecular for by of and globotriaosylceramide PubMed Scopus Google Scholar), that the of under a of Gb3 compared with the in Fabry disease. These Fabry that not in Fabry disease A. M. T. J. S. A Fabry disease mouse by globotriaosylceramide J. PubMed Scopus Google Scholar). in the pathogenesis of Fabry disease is the of in which the of compounds the disease et M. N. A. B. Auray-Blais C. et in Fabry globotriaosylceramide and is by Sci. PubMed Scopus Google in Fabry and accumulation of Gb3 species in Fabry mouse tissues and a of Gb3 in tissue in Fabry to However, all the Gb3 isoforms are increased in Fabry compared with which Gb3 species are responsible for the disease. The background of Fabry that from the of T. J.M. Y. I. R.O. et A deficient a of Fabry disease.Proc. Natl. Acad. Sci. USA. PubMed Scopus Google was a of C57BL/6 (B6) and strains M. S. R. cardiac and renal hypertrophy in Fabry PubMed Scopus Google Scholar). and to we Fabry to the found that Fabry in a pure compared with in a mixed The significantly of disease and of these two strains of Fabry a to the of and disease severity. In this study, we the between tissue levels of various species and Fabry disease in these two mouse strains. In to the of Gb3 in small-fiber we of Gb3 in sensory neuron of dorsal root ganglion (DRG) in Fabry were and approved by the and of The Fabry mouse was from the of T. J.M. Y. I. R.O. et A deficient a of Fabry disease.Proc. Natl. Acad. Sci. USA. PubMed Scopus Google Scholar), which was a mixed background M. S. R. cardiac and renal hypertrophy in Fabry PubMed Scopus Google Scholar). 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These suggest that particular species of Gb3 and lyso-Gb3 may play roles in the pathogenesis of cardiac The of Gb3 and lyso-Gb3 species were in the heart, not in kidneys and that these are not These species may as compared with Gb3 or with a clinical that levels of lyso-Gb3 analogs were with the in Fabry with a cardiac C. M. A. with clinical in Fabry disease with a cardiac 2017; PubMed Scopus Google Scholar). The of fatty acid function of Gb3 has by of PubMed Scopus Google Scholar). Gb3 as a for The binding of to Gb3 is fatty acid A. B. function is by fatty acid and ceramide fatty acid Chem. PubMed Google Scholar, PubMed Scopus Google Scholar). to the in the binding of Gb3 isoforms to increased with fatty acid and for fatty acid species A. B. function is by fatty acid and ceramide fatty acid Chem. PubMed Google Scholar). is that fatty acid of are an in the of of and as as a variety of in E. in cell PubMed Scopus Google Scholar). and fatty acid to these J. 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Fabry disease in disease caused by PubMed Scopus Google Scholar), that the function of Gb3 is in Fabry that the of accumulated Gb3 in and not of Gb3 the deficiency in Fabry E. S. S. N. Wang et deficiency in the pathogenesis of Fabry 2017; PubMed Scopus Google Scholar), that the Gb3 in may more to the pathogenesis lysosomal these we in the Fabry-B6/129 mouse heart, the increased of Gb3 in may of that fatty for to and subsequent cardiac is of the that in this disease is by and and is to these fatty acid moieties Y. T. to Chem. PubMed Scopus Google Scholar). and of in Fabry mouse and the heart E. S. S. N. Wang et deficiency in the pathogenesis of Fabry 2017; PubMed Scopus Google Scholar, L. J. S. J. in a mouse of Fabry PubMed Scopus Google Scholar, L. and in the of deficient in J. 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Trottein F. et al.Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals.Proc. Natl. Acad. Sci. USA. 2007; 104: 5971-5976Crossref PubMed Scopus (133) Google Scholar). lysosomal in Fabry mouse DRG were when Gb3 and were Fabry with the deficient for Gb3 and not by of Gb3 S. R. L. of and the of Fabry PubMed Scopus Google Scholar). In contrast, in the heart, kidney, and the lysosomal were by of Gb3 is that may accumulated in nonpeptidergic nociceptors, to of this that to is the of in Fabry mouse DRG The of that nonpeptidergic from glycolipids, glycoproteins, or has that for of these L. S. 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Gb3 and lyso-Gb3 species with particular fatty acid and sphingosine not Gb3 or with cardiac that compounds may play major roles in the disease and that Gb3 or may not as of the between species and disease and cell not the of Gb3 and lyso-Gb3 in the renal and in Fabry that substrates may play roles in these tissues. the accumulated in DRG an in the of and of this may a for the of neuropathy in Fabry disease. are the and The are to for and and to for and the with C57BL/6 dorsal root ganglion enzyme replacement therapy α-galactosidase A galabiosylceramide globotriaosylceramide isoglobotriaosylceramide globotriaosylsphingosine in

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