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- W2246254209 abstract "Author(s): Larkin, Paul | Advisor(s): Muchowski, Paul J; Mucke, Lennart | Abstract: Many studies of immune responses in neurodegeneration assert that neuroinflammation is a double edged sword - i.e. some aspects of an immune response are beneficial while others are detrimental. In this thesis we investigated two enzymatic cascades that are activated in response to inflammatory stimuli and that we hypothesized were relevant for Huntington's Disease (HD).In Chapter 2 we explored the role of the complement cascade in the R6/2 mouse model of HD. The complement cascade is a well characterized immune response mechanism and it is activated in brains of HD patients. Surprisingly, we found that this upregulation of the complement cascade is not mirrored in the R6/2 mouse model of HD, and that genetic deficiency in complement component C3 does not alter disease progression in these mice. This illustrates that normal complement cascade activity is not necessary for disease progression in R6/2 mice, with the caveat that complement activation in HD patients is not faithfully reproduced in this mouse model of HD. In Chapter 3 we turned our attention to a pathway known to be relevant in HD, the Kynurenine Pathway. Here, instead of seeking a link between the pathway and HD, we sought to understand how two types of Kynurenine Pathway activity, basal and immune stimulated, are controlled. We employed mice genetically deficient in either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO) because these two enzymes can catalyze the rate-limiting step of the Kynurenine Pathway. We evaluated the contribution of each enzyme to basal and immune stimulated production of several Kynurenine Pathway metabolites that play a role in a variety of highly prevalent diseases, including HD. TDO deficient mice show evidence of several compensatory changes in basal Kynurenine Pathway metabolism. These changes suggest the existence of important unknown mechanisms that regulate basal Kynurenine Pathway metabolism. In contrast, IDO deficient mice appear to be a useful tool for cleanly blocking inflammation induced increases in brain Kynurenine Pathway metabolites without altering basal Kynurenine Pathway metabolism. Both of these results have important implications for development of therapeutics targeting the Kynurenine Pathway." @default.
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- W2246254209 date "2012-01-01" @default.
- W2246254209 modified "2023-09-27" @default.
- W2246254209 title "Immune Activated Pathways in Huntington's Disease" @default.
- W2246254209 hasPublicationYear "2012" @default.
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