Investigating the Molecular Mechanisms of Huntington's Disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterised by abnormal spontaneous movements in addition to cognitive and psychiatric impairment. It is caused by an expanded polyglutamine repeat (CAG) in the huntingtin gene (HTT). Despite identification of the gene over 25 years ago, the exact pathogenic mechanism is unknown, and there are no current treatments that cure or delay onset of this devastating disease. Previous work in the Snell laboratory resulted in the construction of the first large mammalian model of HD, a transgenic sheep termed OVT73. The OVT73 model recapitulates many of the early molecular changes observed in HD, and provides an excellent tool for researching the prodromal stages of HD. This model was used to discover widespread metabolic changes including an elevation in brain urea, also recently identified in patients. In the current study, data from a 5-year-old cohort of OVT73 animals has been combined in a 'multi-omic' data platform for use as a public resource for HD research. Using this platform, further evidence supporting metabolic and urea cycle disturbances, were discovered. These results led to the investigation of open source transcriptomic data (mouse allelic series and HD striatum) yielding astounding correlations between CAG repeat size and brain urea cycle gene expression, further supporting HTT-mediated urea cycle disruption. Targeted molecular studies were then conducted, with focus on the liver because of its participation in ammonia/urea metabolism. Transcription of select urea cycle genes in the OVT73 liver were found to be altered, providing a link into the potential source of elevated brain urea and neurotoxicity. A direct relationship between huntingtin and the urea cycle was then revealed through both the knockdown of wild-type HTT and overexpression of mutant HTT in a liver-derived human cell line. The combined evidence challenges the dogma that assumes HD is a disease with a functional origin in the brain. I postulate that HD pathogenesis originates in the liver and results in a systemic elevation in urea/ammonia that ultimately causes the neuropathological symptoms. If this hypothesis is correct, drugs that are already in-use, targeting the urea cycle disorders, could be used as a treatment for HD.