Platelet and myeloid cell phenotypes in a rat model of Fabry disease. Issue 8 (28th July 2021)

• Record Type: Journal Article
• Authors: Kanack, Adam J.; Aoki, Kazuhiro; Tiemeyer, Michael; Dahms, Nancy M.
• Is Part Of: FASEB journal. Volume 35:Issue 8(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-28
• Subjects: animal model -- glycobiology -- glycosphingolipids -- lysosomal storage disease; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202001727RR
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Fabry disease results from a deficiency of the lysosomal enzyme ⍺‐Galactosidase‐A (⍺‐Gal A) and is estimated to occur in approximately 1:4100 live births. Characteristic of the disease is the accumulation of α‐Gal‐A substrates, primarily the glycosphingolipids (GSLs) globotriaosylceramide and globotriaosylsphingosine. Thrombotic events are a significant concern for Fabry patients, with strokes contributing to a significant decrease in overall lifespan. Currently, the mechanisms underlying the increased risk of thrombotic events experienced by Fabry patients are incompletely defined. Using a rat model of Fabry disease, we provide an improved understanding of the mechanisms linking GSL accumulation to thrombotic risk. We found that ⍺‐Gal A‐deficient rats accumulate myeloid‐derived leukocytes at sites of GSL accumulation, including in the bone marrow and circulation, and that myeloid‐derived leukocyte and megakaryocyte populations were prominent among cell types that accumulated GSLs. In the circulation, ⍺‐Gal A‐deficient rats had increases in cytokine‐producing cell types and a corresponding elevation of pro‐inflammatory cytokines. Lastly, circulating platelets from ⍺‐Gal A‐deficient rats accumulated a similar set of ⍺‐Galactosidase‐A substrates as was observed in megakaryocytes in the bone marrow, and exhibited increased platelet binding to fibrinogen in microfluidic and flow cytometric assays.