UBC Theses and Dissertations
Investigating the role of Indoleamine 2,3 dioxygenase in Huntington disease Mazarei, Gelareh
The striatum is predominantly affected in Huntington disease (HD). To address this selective degeneration, we previously studied the gene expression profile in mouse brain and compared the striatum to other brain regions to identify novel striatal-enriched genes. One identified gene was Indoleamine 2,3 dioxygenase (Ido1), the first and the rate-limiting enzyme of the kynurenine pathway (KP), which was differentially expressed in the striatum of YAC128 mouse model of HD. KP leads to the production of both neuroprotective and neurotoxic metabolites, the imbalance of which has been implicated in several neurodegenerative disorders. This PhD thesis initially focuses on the age-dependent changes of the KP in YAC128 mice with a main focus on Ido1 expression and activity. I was able to demonstrate a chronic induction of Ido1 expression and activity in the striatum of YAC128 mice, which correlated with different substrate or product levels during the course of the disease. Using a liquid chromatography mass spectrometry method, I was also able to identify changes in the downstream metabolites, which seemed to follow a biphasic pattern where neurotoxic metabolites were reduced in presymptomatic mice and increased in symptomatic mice. We propose that the striatal-specfic induction of Ido1 and downstream KP alterations suggest involvement in HD pathogenesis, and should be taken into account in future therapeutic developments for HD. To follow up, this thesis project also assesses the sensitivity of brain to NMDA-mediated excitotoxicity in the absence of Ido1 expression under in vivo and ex vivo settings. I was able to demonstrate decreased sensitivity to NMDA receptor-mediated neurotoxicity in the brain of Ido1 constitutive null mice compared to that of WT. These data suggest that lack of Ido1 expression in vivo provides protection against NMDA-receptor-mediated excitotoxic stress, a well-described mechanism in HD pathogenesis.
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