Therapeutic effects of ganlgioside GM1 and gangliomimetic compounds in multiple models of Huntington disease

• Author / Creator

  Alpaugh, Melanie J

• Huntington disease (HD) is a neurodegenerative disorder that results in motor, cognitive and psychiatric deficits. The disease is caused by the expansion of a polyglutamine stretch in huntingtin (HTT), a ubiquitous protein with unclear functions. The molecular mechanisms underlying neurodegeneration in HD are complex and include transcriptional dysregulation, mitochondrial dysfunction, impaired intracellular and axonal transport, as well as aberrant cell signaling and neurotransmission. Previous work showed that the synthesis of ganglioside GM1, a lipid highly enriched in the brain, is also impaired in HD models. Decreased levels of GM1 contribute to heightened HD cells susceptibility to apoptosis, and chronic intra-ventricular infusion of GM1 reverts the pathological motor phenotype in already symptomatic transgenic models of HD. The dramatic therapeutic effects of GM1 are accompanied by phosphorylation of mutant huntingtin (mHTT) at Ser13 and Ser16, a post-translational modification that has been shown to decrease mHTT toxicity. This suggests that GM1 might be able to modify the course of HD and to provide therapeutic benefits that go beyond the treatment of motor symptoms. To test this hypothesis we investigated whether administration of GM1 affects neurodegeneration and disease progression in R6/2 mice, an established model of HD that displays profound motor deficits, early-onset neurodegeneration and premature death. In these mice, treatment with GM1 resulted in improved motor performance, accompanied by a significant attenuation of the neurodegenerative process. GM1 reduced the loss of striatal neurons and increased overall brain and striatal volume. In addition, GM1 displayed trophic effects on the brain white matter and restored the volume of the corpus callosum to normal levels. Next, we determined whether GM1 improves cognitive and psychiatric-like symptoms in YAC128, a second transgenic model of HD, and Q140 mice, a knock-in mouse model. Both models display a slower disease progression, with respect to R6/2 mice, allowing for a more accurate analysis of non-motor behaviour. Significant attenuation of cognitive and psychiatric-like symptoms was observed in YAC128 mice after 14 days of treatment and in Q140 mice after 28 days of treatment with GM1. Both models returned to WT performance levels on tests of anxiety, cognition, and depression, when treated with GM1. One issue that could limit the therapeutic use of GM1 is its poor ability to cross the blood-brain barrier (BBB). Although intra-ventricular or intra-thecal administration of GM1 is feasible, development of “gangliomimetic” therapies that can be administered peripherally is highly desirable and would greatly accelerate the development of a therapy for HD. As a first step towards the identification or design of gangliomimetic compounds with improved pharmacokinetic profile, we have screened natural gangliosides and strategically designed gangliomimetic compounds to identify the key chemical structure/s required to recapitulate the neuroprotective effects of GM1 in models of HD. Using an in vitro assay to measure cell apoptosis, we have identified compounds with similar or increased potency with respect to GM1. In preliminary studies, one of these compounds provided therapeutic benefits in an HD mouse model after intraperitoneal injection for 28 days. Overall, my thesis shows that the therapeutic effects of GM1 extend beyond amelioration of motor symptoms and support the hypothesis that GM1 has disease-modifying properties in HD models. Furthermore, my thesis supports the idea that second generation compounds can be developed with improved administration profiles while maintaining similar efficacy.

• Subjects / Keywords

  • Huntington disease
  • Gangliosides
  • GM1

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3HX16687

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.