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http://hdl.handle.net/11375/20541
Title: | MECHANISMS OF NEURODEGENERATION IN A MOUSE MODEL OF SANDHOFF DISEASE: ROLES OF INFLAMMATION, EXCITOTOXICITY, AND APOPTOSIS |
Other Titles: | MECHANISMS OF NEURODEGENERATION IN A MOUSE MODEL OF SANDHOFF DISEASE |
Authors: | Hooper, Alexander William Maurice |
Advisor: | Igdoura, Suleiman |
Department: | Biology |
Keywords: | Sandhoff;Tay-Sachs;Neuronal Pentraxin 1;TNF-alpha;Neurodegeneration;GluR1;Microgliosis;Astrogliosis;NP1-38;Bi-Phasic |
Publication Date: | 2016 |
Abstract: | Lysosomal storage disorders are a group of rare neurodegenerative diseases that are collectively common, sharing many aspects with other neurodegenerative disorders, including substrate build-up and neuroinflammation. The GM2 Gangliosidoses, Tay-Sachs disease and Sandhoff disease, are pathologically overlapping lysosomal storage disorders, with high prevalence within specific ethnicities. Their effects are neurologically devastating and often fatal at young ages. Current treatments only slow or stall an inevitable decline in health. Novel treatment targets are needed for these disorders, and others with similar pathologies. In these works we demonstrate the negative effect the inflammatory cytokine tumour necrosis factor-alpha has on survival of a model of Sandhoff disease. We demonstrate its role in the upregulation of astrogliosis, and apoptosis, and we present evidence that this effect on astrogliosis occurs through an upregulation of the JAK-2/STAT3 pathway. Though fruitful, a singular focus on inflammation/gliosis in these diseases has left a vacuum in the research into neuron specific molecular processes. We observe the development of inflammation, astrogliosis and neuronal processes in our model, and demonstrate a bi-phasic disease progression, in which early onset microgliosis precedes terminal astrogliosis, apoptosis, and a decline in excitatory glutamate receptors, suggesting neuron-specific malfunction. Furthermore, we show that knockout of the synaptic protein neuronal pentraxin 1 retards neurodegeneration and extends the lifespan of Sandhoff disease mice, independent of inflammation or astrogliosis. Through electrophysiology, we provide evidence of dysregulation of glutamate receptors in Sandhoff disease, and show that knockout of neuronal pentraxin 1 provides rescue from this dysregulation. This work expands on research into gliosis in GM2 gangliosidoses, presents the finding of a novel protein isoform, and presents a new focus on non-glial disease mechanisms and treatments for these and other neurodegenerative disorders. |
URI: | http://hdl.handle.net/11375/20541 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Hooper_Alexander_WM_finalsubmission201609_PhD.pdf | 8.31 MB | Adobe PDF | View/Open |
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