Natural History of Tay-Sachs Disease in Sheep
Autor: | Jey W. Koehler, Ashley N. Randle, Jillian Gallagher, Amanda L. Gross, Elise B. Diffie, Brett D. Story, Sundeep Chandra, Sara Carl, Kayly Nielsen, Paul Cuddon, Miguel Sena-Esteves, Edwin H. Kolodny, Deborah Fernau, Amanda R. Taylor, Douglas R. Martin, Carly Corado, Xuntian Jiang, Heather L. Gray-Edwards, Annie S. Maguire, Toloo Taghian, Siauna Johnson |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
endocrine system
medicine.medical_specialty Endocrinology Diabetes and Metabolism Physiology Disease Biochemistry Article White matter Endocrinology Genetics Medicine Animals Molecular Biology Pathological Sheep Tay-Sachs Disease business.industry Neurodegeneration Tay-Sachs disease Brain medicine.disease Magnetic Resonance Imaging Pathophysiology Disease Models Animal medicine.anatomical_structure Biomarker (medicine) Histopathology business |
Zdroj: | Mol Genet Metab |
Popis: | Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme β-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients. |
Databáze: | OpenAIRE |
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