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MT1 receptor mediated neuroprotection in R6/2 mouse model of Huntington's disease
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MT1 receptor mediated neuroprotection in R6/2 mouse model of Huntington's disease
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Dissertation
MT1 receptor mediated neuroprotection in R6/2 mouse model of Huntington's disease
2016
Overview
Huntington’s Disease (HD) is a fatal, autosomal dominant, neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The disease is characterized by chorea, as well as psychiatric and cognitive symptoms. At present, no treatment able to modify the disease progression is available. HD is characterized by the death of medium striatal spiny neurons within the brain. Melatonin is a hormone which acts as a neuroprotectant in a variety of neurodegenerative diseases. While most endogenous melatonin is produced by the pineal gland and circulated in the bloodstream, melatonin is also present in neurons. Here I use a novel method of detecting site specific melatonin synthesis to show melatonin is synthesized in neuronal mitochondria, where melatonin receptors are also localized. Previous research shows the melatonin receptor MT1 to be the mechanism of melatonin’s neuroprotection in cell and mouse models of HD. Here I measure the expression of MT1 in the R6/2 mouse model of HD to compare with literature reported decrease in expression, and test the effects of the R6/2 phenotype on overexpression of MT1 in a transgenic MT1 mouse model (NSE-MT1). Further, I use the cross of the NSE-MT1 mouse model and R6/2 to assess the effects of overexpression of MT1 in increasing melatonin’s neuroprotective properties to ameliorate disease phenotypes including caspase activation, neuronal density, rotarod behavioral testing, and survival. Together, these data show overexpression of MT1 produces small increases in melatonin’s neuroprotective properties with regard to caspase activation, but this protective effect does not cause corresponding increases in behavioral deficits or survival. Neuroprotection by melatonin is partially mediated by the MT1- receptor in an HD mouse model, but may additionally function by alternate pathways or be modulated by regulatory mechanisms. Understanding melatonin’s role as a neuroprotectant can help with the development of melatonergic therapeutics to treat HD and other neurodegenerative diseases to significantly impact public health outcomes.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9781369321999, 1369321996
