RNA-seq analysis of 6 human and 6 mouse striatum samples: 3 control human subjects and 3 Huntington's disease patients, together with 3 control (wild type) mice and 3 early symptomatic R6/1 mice. The RNA-seq libraries were prepared with KAPA Stranded mRNA-Seq Illumina® Platforms Kit (Roche) and were sequenced on HiSeq 2500 (Illumina, Inc) with a read length of 2x101bp.. Huntington’s disease-specific mis-splicing unveils key effector genes and altered splicing factors

Next-generation RNA sequencing (RNAseq) has boosted investigation of global mis-splicing in diseased tissue. Nevertheless, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington’s disease (HD) pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the HD-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked mis-spliced effector genes. This new intersect-RNA-seq approach that can be readily applied to other neurodegenerative diseases for which bona fide animal models are available.