Natural history study of glycan accumulation in large animal models of GM2 gangliosidoses

Autor: Emma McCullagh, Linley Mangini, Carley R. Corado, Jeremy L. Van Vleet, Roger Lawrence, Douglas R. Martin, Heather L. Gray-Edwards, Brett E. Crawford, Catlyn Cavender
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Physiology
Urine
Biochemistry
Gangliosidoses
0302 clinical medicine
Gangliosidoses
GM2
Medicine and Health Sciences
Metabolites
Phospholipids
Mammals
Cerebral Cortex
Multidisciplinary
biology
Tay-Sachs disease
Eukaryota
Brain
Ruminants
Lipids
Body Fluids
medicine.anatomical_structure
Vertebrates
Medicine
Occipital Lobe
Anatomy
Research Article
Genetic diseases
Medical conditions
Glycan
Science
Sandhoff disease
03 medical and health sciences
Polysaccharides
Lysosome
medicine
Animals
Clinical genetics
Phospholipidosis
Sphingolipids
Sheep
GM2 gangliosidoses
Organisms
Biology and Life Sciences
medicine.disease
Sphingolipid
carbohydrates (lipids)
Disease Models
Animal
Metabolism
030104 developmental biology
Autosomal recessive diseases
Amniotes
Cats
biology.protein
Zoology
030217 neurology & neurosurgery
Zdroj: PLoS ONE, Vol 15, Iss 12, p e0243006 (2020)
PLoS ONE
ISSN: 1932-6203
Popis: β-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing β-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by β-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders.
Databáze: OpenAIRE
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