A046 Uncovering the pathobiology of polyglutamine-expanded huntingtin in Huntington’s disease

<h3></h3> The major current challenge in disease research is to understand the causative molecular events and to predict the clinical manifestations of pathogenic genetic variants. This is true for complex diseases with multiple disease-associated genetic variants like cancer but also for monogenic diseases such as Huntington’s disease (HD) where a single causative mutation in one specific gene drives the disease process. We apply quantitative multi-OMICs techniques, disease-relevant experimental model systems and network modelling approaches to investigate the normal molecular function of full-length huntingtin (HTT) in cells. In addition, the impact of small HTT exon-1 (HTTex1) fragments with pathogenic, aggregation-prone polyglutamine (polyQ) tracts on critical neuronal functions is assessed in transgenic Drosophila melanogaster strains. Our studies indicate a striking correlation between the formation of self-propagating amyloidogenic HTTex1 aggregates in neurons and the shortening of the flies’ lifespan. Furthermore, the self-assembly of HTTex1 aggregates with long pathogenic polyQ tracts in neurons is associated with sequestration of multiple synaptic vesicle proteins and a transcriptional down-regulation of genes controlling neurotransmitter synthesis and release in neurons. Finally, a machine learning approach using RNAseq data highlighted multiple lifespan-predicting genes with crucial functions in neuronal communication. Our studies support the hypothesis that HD is a ‘polyglutamine-opathy’ in which small, self-propagating, neurotoxic mutant HTT aggregate species with very long polyQ tracts play a central role in disease development and potentially drive impairment of crucial synaptic functions and progressive neurodegeneration in HD patient brains.