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http://hdl.handle.net/11375/21662
Title: | Molecular mechanisms of Tay Sachs Disease: calcium, excitotoxicity, and apoptosis |
Authors: | King, John-Paul |
Advisor: | Igdoura, Suleiman |
Department: | Biology |
Keywords: | Molecular mechanisms;Tay Sachs Disease;calcium;excitotoxicity;apoptosis |
Publication Date: | Aug-2007 |
Abstract: | <p> The objective is to investigate the molecular mechanisms leading to neurodegeneration in Tay Sachs disease, a lysosomal storage disorder caused by a deficiency in the enzyme hexosaminidase A. This was accomplished using microarray analysis of normal and Tay Sachs neuroglia. Microarray data analysis was performed using Onto Express, PANTHER software, and cluster analysis. The expression levels of selected genes were validated using Real Time PCR. To establish a physiological relationship between GM2 accumulation and the expression of these genes, their expression was assessed after treatment with an inhibitor of ganglioside synthesis, nbutyldeoxynojirimycin (NBDNJ). Neuronal pentraxin 1 (NPTX1), potassium channel, subfamily K, member 2 (KCNK2), and prostaglandin synthase 1 (PTGS 1) were found to be upregulated in Tay Sachs neuroglia while heme oxygenase (HMOX1) was downregulated. The mRNA levels ofNPTX1, KCNK2, PTGS1, and HMOX1 all reverted to normal levels in response to ganglioside synthesis inhibitor. Pentraxin RNA levels were also reduced in response to sialidase overexpression, another method of GM2 reduction. Pentraxin protein levels were also increased in Tay Sachs cells in response to u-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA), and were attenuated upon treatment with either NBDNJ or AMPA antagonist 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo [f]quinoxaline-2,3-dione (NBQX). Strong colocalization was seen between NPTX1 and the AMPA receptor as well as the glutamate transporter EAACI. AMP A receptor function was also enhanced as illustrated by an increase in calcium influx upon stimulation. This stimulation also resulted in increased apoptosis during AMPA receptor stimulation. In this study, our genetic profiling experiment led to the identification of NPTXl as a marker of pathogenesis in Tay Sachs Cells. The role of NPTXl in excitotoxicity implicates the latter in disease mechanism associated with Tay Sachs disease. Furthermore, this study provides evidence that TSD cells undergo programmed cell death in response to increased intracellular calcium as a result of increased glutamate receptor stimulation. </p> |
URI: | http://hdl.handle.net/11375/21662 |
Appears in Collections: | Digitized Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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King_John-Paul_A_C_Masters.pdf | 6.28 MB | Adobe PDF | View/Open |
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