a pathogenic mechanism in huntingtons disease involves small cag-repeated rnas with neurotoxic activity亨廷顿氏病的发病机理涉及小cag-repeated rna毒害神经的活动.pdfVIP

A Pathogenic Mechanism in Huntington’s Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity ´ ˜ 1,2 1,3 1,2 1,2 Monica Banez-Coronel , Silvia Porta , Birgit Kagerbauer , Elisabet Mateu-Huertas , 1,2 3,4 ´ 4,5 1,2 ` ´1,2 Lorena Pantano , Isidre Ferrer , Manuel Guzman , Xavier Estivill *, Eula lia Martı * 1 Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Universitat Pompeu Fabra, Barcelona, Catalonia, Spain, 2 Network of Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain, 3 Institute of Neuropathology, IDIBELL-Bellvitge University Hospital, L’Hospitalet de Llobregat, Catalonia, Spain, 4 Network of Biomedical Research in Neurodegenerative Disorders (CIBERNED), Madrid, Spain, 5 Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain Abstract Huntington’s disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of 21