Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice

• Published in: Neuron (Cambridge, Mass.) Mass.), 2022-04, Vol.110 (7), p.1173-1192.e7
• Main Authors: Gu, Xiaofeng, Richman, Jeffrey, Langfelder, Peter, Wang, Nan, Zhang, Shasha, Bañez-Coronel, Monica, Wang, Huei-Bin, Yang, Lucia, Ramanathan, Lalini, Deng, Linna, Park, Chang Sin, Choi, Christopher R., Cantle, Jeffrey P., Gao, Fuying, Gray, Michelle, Coppola, Giovanni, Bates, Gillian P., Ranum, Laura P.W., Horvath, Steve, Colwell, Christopher S., Yang, X. William
• Format: Article
• Language: English
• Subjects: aggregation; Animals; BAC transgenic; BAC-CAG; BACHD; CAG repeat; Chromosomes, Artificial, Bacterial - genetics; Chromosomes, Artificial, Bacterial - metabolism; Disease Models, Animal; Humans; Huntingtin; Huntingtin Protein - genetics; Huntington Disease - genetics; Huntington Disease - pathology; Huntington’s disease; instability; knockin; Mice; Mice, Transgenic; motor deficits; muscleblind; mutant huntingtin; Nerve Tissue Proteins - genetics; Neurons - metabolism; nuclear inclusions; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; polyglutamine; RAN translation; RNA foci; RNA-seq; striatum; transcriptional dysregulation; transcriptionopathy; Trinucleotide Repeat Expansion - genetics
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.01.006

In Huntington’s disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively. [Display omitted] •A novel human mHTT BAC transgenic model of HD with long uninterrupted CAG repeats•BAC-CAG shows striatum-selective pathogenesis that evaded previous mHTT models•Uninterrupted mHTT CAG repeat length is key to striatal transcriptionopathy in HD•Repeat instability and nuclear mHTT best correlate with striatal disease onset Using a novel human genomic BAC transgenic mouse model of HD with long uninterrupted CAG repeats, Gu et al. provided molecular, pathological, and behavioral data to demonstrate critical pathogenic roles of uninterrupted CAG repeats in mutant HTT, beyond its encoded polyglutamine protein, in eliciting striatum-selective pathogenesis in vivo.