Sandhoff disease (SD), a fatal lysosomal storage disease, results from a deficiency of the β-subunit of the β-hexosaminidase A and B enzymes. This deficiency leads to severe accumulation of GM2 gangliosides in lysosomes within the central nervous system (CNS) resulting in mass neuronal apoptosis. The mouse model of SD shows progressive neurodegeneration that closely resembles Sandhoff and Tay Sachs disease (TSD) in humans. SD and TSD consist of infantile, juvenile, and late-onset forms. These diseases can present with a multiplicity of symptoms including cognitive and speech impairments, ataxia, and lower motor neuron disease. Late-onset SD and TSD show motor neuron disease in over 40% of patients. In this study, we explore the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the spinal cord during the development and progression of disease in Sandhoff mice. Using immunocytochemistry and western blotting, we analyzed the expression level and localization of several ER stress and cellular apoptosis markers within the cervical, thoracic, and lumbar regions of the spinal cord of Sandhoff mice. Our results revealed significant upregulation of several ER stress markers in motor neurons that appeared to coincide with significant lysosomal accumulations. In addition, we observed sequential and age-dependent expression changes in ATF6 and CHOP and their prominent nuclear localization within anterior horn motor neurons. Markers of apoptosis, caspases and PARP also appeared to be activated in the spinal cords of Sandhoff mice starting as early as 60 days. Interestingly, we noted more than 50% reduction in neuronal numbers in all regions of the spinal cord of Sandhoff mice between ages 80 and 120 days. Overall, this study provides strong evidence for the role of chronic ER stress and UPR activation in the spine pathophysiology of SD. / Thesis / Master of Science (MSc) / Lysosomal storage diseases are a rare group of inherited neurological disorders that are often fatal at a young age. Two diseases that fall within this category, Sandhoff and Tay Sachs disease, are similar in their cause and symptoms. Current research lacks a complete understanding of the mechanism behind these disorders making the development of new therapeutics challenging. This research highlights a group of cells in the spine that are vulnerable in these diseases. These cells show physical and functional changes in their structure as the diseases progress. We provide evidence of a new stress pathway which appears to be strongly implicated in the development and progression of these diseases. We also show an association between this pathway and the death of these vulnerable cells leading to the symptoms exhibited by patients. These findings expand our current knowledge of these disorders and open new avenues for therapeutic interventions.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27278 |
| Date | January 2022 |
| Creators | Weaver, Fiona |
| Contributors | Igdoura, Suleiman, Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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