Date of Award
Master of Science
Molecular, Cellular and Developmental Biology
N. Matthew Ellinwood
The mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases (LSDs) which are characterized by the aberrant primary storage of glycosaminoglycans (GAGs) in lysosomes of multiple organ and tissue systems. The most commonly diagnosed is MPS Type I (MPS I), caused by mutations in the gene which codes for α-L-iduronidase (IDUA). Biochemically, MPS I is characterized by the aberrant primary lysosomal storage of incompletely degraded dermatan and heparan sulfates, along with a secondary accumulation of gangliosides and other compounds in lysosomes. Its clinical manifestation in severe form leads to early death, characterized by progressive central nervous system disease (with behavioral and cognitive impairment), severe bone and joint abnormalities, respiratory and cardiac impairment, hepatosplenomegaly, coarse facies and corneal clouding. There are three recognized diagnostic clinical categories of MPS I: Hurler (severe), Hurler-Scheie (intermediate) and Scheie (attenuated) across differing levels of IDUA activity. Treatment strategies addressing the etiological cause include the restoration of enzyme activity and substrate deprivation, while symptomatic therapy involves management of secondary immunological effects and surgical amelioration of symptoms. Animal models of the disease have been integral to understanding pathology, disease progression, and the development of treatments.
To explore the impact of secondary accumulating products in the pathology of neuronopathic MPS diseases, Mohammed et al. (2012) created double knockout mouse models of MPS IIIA and IIIB and β-1,4-N-acetylgalactosaminyltransferase (GalNAcT) deficiency – an enzyme responsible for the synthesis of complex gangliosides. The double knockouts exhibited an accelerated progression of the disease and a severely shortened lifespan. The aim of this project was to find out if such an accelerated neuropathology is also seen in MPS I/GalNAcT double knockout mice and to characterize MPS I neuropathology in an animal model with accelerated CNS pathology.
Our findings so far show an accelerated disease progression and early death in the double knockout compared to the single knockout mouse based on the observed clinical signs and gross observations on dissection. Future work will involve obtaining more double knockouts and conducting a thorough biochemical, histological, and behavioral analysis to achieve statistically significant results. Such double knockout mice may provide a better understanding of the neuropathology of the disease and be useful in rapid testing of therapeutic strategies.
Gera, Karan, "Characterization of a Mucopolysaccharidosis Type I and GalNAc Transferase deficiency double knockout mouse" (2018). Graduate Theses and Dissertations. 16582.