Cell reports · 2025
A human CAGinSTEM platform for decoding HTT repeats' somatic instability links CAG interruption to HD pathology in neurons.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zobel Martina, Damaggio Gianluca, Mignogna Maria Lidia, Besusso Dario, Scalzo Davide, Cossu Andrea, Trovesi Camilla, Crosti Mariacristina, Cortina Francesco, Campus Ilaria, Formenti Giulio, Mazzara Saveria, Gregoretti Francesco, Antonelli Laura, Oliva Gennaro, Zuccato Chiara, Colonna Vincenza, Conforti Paola, Cereda Matteo, Rossi Riccardo Lorenzo, Maestri Simone, Scolz Andrea, Iennaco Raffale, Cattaneo Elena
Аннотация
Somatic CAG instability in the mutant Huntingtin (HTT) gene is increasingly recognized as a key hallmark of Huntington's disease (HD). Using our novel human CAGinSTEM platform, we manipulated cis genetic elements influencing instability in human HD neurons, monitoring repeat length. Quality-controlled CRISPR-engineered stem cells with increasing CAG lengths and clinical haplotypes were analyzed using third-generation sequencing. Our findings link interruptions in the CAG repeat, especially the loss or duplication of the penultimate CAA of canonical alleles, to significant instability modulation. Notably, four internal CAA interruptions completely abolish CAG instability, reversing HD phenotypes such as altered striatal fate acquisition and nuclear disorganization. This platform highlights the role of cis modifiers, emphasizing the direct influence of HTT DNA repeat composition on CAG instability and providing a robust framework for modeling HTT repeat instability in vitro.