B008 Mutant RNA contributes to neuropathology in new mouse models of Huntington’s disease

<h3>Background</h3> Huntington’s disease results from the expansion of CAG repeats in the huntingtin gene (HTT). The extent to which mutant mRNA-driven disruptions contribute to neurodegeneration in HD is still a subject of debate, particularly in comparison to the dominant mechanisms related to the gain-of-function effects of the mutant polyglutamine protein. <h3>Aim</h3> This study aimed to evaluate the contribution of mutant RNA to HD pathogenesis in vivo. <h3>Methods</h3> We generated two mouse models through a knock-in strategy at the Rosa26 locus. These models expressed distinct variants of human mutant HTT cDNA fragment: a translated variant (HD/100Q model) and a nontranslated variant (HD/100CAG model). HTT transgene contained additional sequences, namely, an HA tag and MS2 aptamer, facilitating the detection of the protein and transcript, respectively. The cohorts of animals were subjected to a broad spectrum of molecular, behavioral and cognitive analysis for 21 months. <h3>Results</h3> Behavioral testing revealed a progressive phenotype in both models, with the HD/100Q model exhibiting a more severe phenotype. The rotarod, static rod and open-field tests showed motor deficits in HD/100CAG and HD/100Q model mice during the light phase, while ActiMot indicated hyperkinesis during the dark phase. Both models also exhibited certain striatal transcriptionopathy. <h3>Conclusion</h3> We provide in vivo evidence for a contributory role of mutant RNA in HD pathogenesis. The separated effects resulting from the presence of mutant RNA in the HD/100CAG model led to less severe but, to some extent, similar types of impairments (such as increased anxiety) as in the HD/100Q model. <h3>Funding</h3> 2012/06/A/NZ1/00094;2015/19/B/NZ2/02453;2015/19/D/NZ5/02183;2016/21/D/NZ4/00478;2021/41/B/NZ3/03803.