B39 Modelling and biological evidence for alteration of extracellular vesicles in huntington’s disease

Intercellular communication mediated by extracellular vesicles (EV) is emerging as a mechanism that is important to neuronal homeostasis and integrity. However, there is little information available on the importance of EV signalling in response to proteotoxic stress in Huntington’s disease (HD). Using network methods to integrate HD gene expression datasets across model species, we developed a computational model of the transition from the early (cell differentiation) to intermediate (dysfunctional striatum) and late (advanced neurodegeneration) phases of HD. This model indicates that genes associated to extracellular vesicular exosomes are impacted across biological phases, raising the possibility that EV signalling may be altered in cells expressing mutant huntingtin. To test for this, we analysed EVs in mouse striatal cells derived from the HdhQ111 knock-in mice. In studies of EVs, it is important to discriminate different subtypes of EVs based for example on size and intracellular origin as this may determine function. In these experiments, we used protocols and EV markers that allow for the differential analysis of EV subtypes to be performed, testing for changes in protein content and level of secretion. The results suggest that specific EV populations may be altered in cells expressing mutant huntingtin.