Investigating the Role of Physiological Systems Outside the Central Nervous System on Huntington's Disease Pathogenesis

AbstractInvestigating the Role of Physiological Systems Outside the Central Nervous System on Huntington's Disease PathogenesisBy Jill LarimoreHuntington's disease (HD) is a devastating neurodegenerative disease for which there is no cure. Classically, HD is thought to result from central nervous system (CNS) dysfunction because its hallmark pathology is neurodegeneration of brain regions important for controlling movement. However, co-occurring pathologies, including severe weight loss and peripheral immune system activation, might contribute to HD progression. Given that the mutant Huntingtin protein (mHtt) is ubiquitously expressed and directly affects cells outside the CNS, an integrated understanding of mHtt-induced pathogenesis is needed. In this dissertation, I sought to understand how both central nervous and peripheral physiological systems contribute to HD pathogenesis by taking advantage of the endocannabinoid system, in which the two main cannabinoid receptors, CB1 and CB2, have distinct roles. In chapter 2, I investigated the role of CB1, which is primarily expressed in the CNS and whose expression is one of the earliest genetic changes to occur in HD-vulnerable neurons, on HD progression. We found that early genetic deletion of CB1 receptors in R6/2 mice accelerated the onset of symptoms and further decreased lifespan compared to CB1-receptor-expressing R6/2 mice, suggesting CB1 plays a functional role in HD progression. In chapter 2.1, I investigated the effects of animal weight on HD progression in BACHD mice, an overweight HD model. Specifically, using ANCOVA as a robust statistical tool, I found that changes in weight induced by deletion of CB1 expression significantly influenced HD behavior. In chapter 3, we investigated the peripheral immune system, showing that genetic deletion of CB2 in a slow-progressing HD mouse model accelerated the onset and increased the severity of motor deficits. Treatment of mice with a CB2-receptor agonist extended lifespan and suppressed motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB2-receptor antagonist blocked these effects. CB2 regulates blood interleukin-6 levels, and interleukin-6-neutralizing antibodies partially rescued motor deficits and weight loss in HD mice. These findings support a causal link between CB2-receptor signaling in peripheral immune cells and the onset and severity of HD-induced neurodegeneration. Together, these results demonstrate that mHtt can significantly impact peripheral physiological systems, and identify novel therapeutic approaches for treating HD