Gene-environment interactions between mutant huntingtin and manganese exposure alter striatal neurochemistry and medium spiny neuron morphology.

Abstract

Huntington’s disease is a fatal autosomal dominant neurodegenerative disease caused by an expansion of CAG repeats in the DNA of the Huntingtin gene. The length of the repeat is inversely related to the age of disease onset, however it only accounts for 60% of the variability in the age of onset. Therefore, other genetic and environmental effects contribute to the remaining 40% in the variability in age of onset. Multiple neurodegenerative diseases exhibit alterations in metal ion homeostasis. Research in our laboratories has demonstrated a disease-toxicant interaction between mutant Huntingtin and manganese exposure in vitro. Manganese is an essential trace metal that is necessary for many physiological processes, including neurotransmitter synthesis. In high levels, manganese can be damaging to the brain. Exposure that leads to this damage is typically encountered in an occupational setting such as when welding, smelting or mining manganese.

The research described in this dissertation is the first to describe the complex gene-environment interactions between mutant Huntingtin and manganese exposure in vivo. The neurochemical and morphological changes identified herein are complex and exhibit both positive and negative effects. My research also identified the earliest evidence for striatal dendritic pathology in YAC128 mice that occur between 13 and 16 weeks postnatal. Additionally, this is the first research to show gender-specific changes in MSN morphology following manganese exposure. These alterations in neuron morphology were most prevalent when manganese levels were elevated and were not due to differential striatal manganese accumulation.

Taken together, these data lay the groundwork for understanding the gene-environment interaction between mutant Huntingtin and Mn exposure. Future studies will further our understanding of this interaction that may one day lead to therapeutic intervention. These studies also reinforce the need to include animals of both genders in experimentation to further our understanding of disease across both genders.