Graduation Year
2019
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Roger Lawrence, PhD
Second Reader
Kenneth Frost, PhD
Abstract
β-N-acetylhexosaminidase B, or just β-hexosaminidase, is an enzyme responsible for the degradation of gangliosides, glycans and other glycoconjugates in the lysosome. The gene HEXA encodes the α-subunit and HEXB encodes the β-subunit of the β-hexosaminidase enzyme which functions as a dimer pair either as a heterodimer, Hex A (αβ), or homodimer, Hex B (ββ) or Hex S (αα). GM2 gangliosidoses, like Tay-Sachs and Sandhoff, are lysosomal storage diseases characterized by a disruption in the β-hexosaminidase genes. The loss of β-hexosaminidase activity results in the toxic accumulation of substrate metabolites. Tay-Sachs is caused by a disruption in the HEXA gene causing a deficiency in the Hex A enzyme. Sandhoff, is due to a disruption in the HEXB gene causing a deficiency in the Hex A and Hex B enzymes. Both diseases accumulate GM2 gangliosides, but Sandhoff accumulates free oligosaccharides as well because the β-subunit is required for their degradation. Ganglioside and glycan levels in both tissues and biological fluids from two large animal models, Sandhoff feline and Tay-Sachs sheep, were longitudinally examined for a natural history study. Sandhoff cats accumulated the same amount of gangliosides as the Tay-Sachs sheep, but at a much quicker rate, and accumulated glycan metabolites. This large animal natural history for Sandhoff and Tay-Sachs gives more insight into the progression of these diseases at the biochemical level. These results are more relevant to humans compared to other animal models because of their similarities to human pathology and thus, may help in the development of new therapeutics to treat these and similar disorders.
Comments
A modified version of this work is currently being submitted for publication.