Project Summary HD is an autosomal dominant neurodegenerative disease, characterized by movement, cognitive and emotional disorders, with relentless progression to death. There is currently no disease-modifying treatment for HD. Though clinical suppression strategies are in clinical trials or preclinical development, the efficacy and tolerability of these treatments remains unknown, hence there is great need to search, in parallel, for other therapeutic targets. To facilitate prioritizing HD pathways for therapeutic interventions, we have launched an effort to compare HD with Huntington’s disease-like 2 (HDL2). HDL2, discovered and genetically defined by our group, is an adult onset autosomal dominant neurodegenerative disorder that is clinically, genetically, and neuropathologically remarkably similar to HD. Experts cannot distinguish between the two disorders without genetic testing. Both disorders are caused by a repeat expansion mutation; the mutation in HDL2 is caused by a CTG/CAG expansion on chromosome 16q24 in the gene junctophilin-3. Like HD, expanded tracks of polyglutamine probably are the key factor in HDL2 pathogenesis. However, also like HD, RNA transcripts containing the expanded repeat and a loss-of- function the gene in which the repeat is found likely also contribute to pathogenesis. We hypothesize that HD and HDL2 share pathogenic pathways, and that detecting these pathways will lead to further understanding of both disorders and the development of new therapeutic targets. As part of our efforts to test this hypothesis, we propose to use CRISPR/Cas9 and ssDNA donors to generate an HDL2 knock-in (KI) mouse model with either 14 (normal) or ~100 triplets (mutation). We will compare these new mouse lines with the similar KI HD lines Hdh10/+ and HDh111/+. In Aim 1, we will test the hypothesis that the HDL2 and HD expansion mutations results in a similar phenotype by comparing the behavior and neuropathology of HDL2 and HD KI lines. In Aim 2, we will test the hypothesis that similar molecular mechanisms are associated with HD and HDL2 pathogenesis by using RNAseq to compare the pattern of gene expression in the HDL2 and HD model mice. If successful, this project will provide the basis for detailed studies designed to find new therapeutic targets for both HD and HDL2.