Transcriptomic hallmarks and RNA isoform diversity in human neurodegenerative disease

Single-cell RNA-sequencing (scRNA-seq) has enabled high-throughput RNA analysis at an unprecedented resolution. One staple analysis in scRNA-seq is identifying differentially expressed genes (DEGs) between two populations. However, the mRNA isoforms have often been overlooked in these transcriptomic analyses due to technical limitations. In order to investigate the mRNA isoforms at the single-cell level, we used a targeted single-nucleus long-read RNA-sequencing method combining single-nucleus short-read RNA-seq (snRNA-seq), target gene enrichment, and Iso-Seq. We performed snRNA-seq and targeted single-nucleus Iso-Seq (snIso-Seq) on 25 human frontal cortices from individuals with AD, DLB, or PD, and age-matched controls. Our short-read transcriptome analysis revealed that DLB samples had more overlapping DEGs with AD than PD despite sharing pathological hallmarks with PD. We observed vast RNA isoform diversity in the 50 genes targeted, including genes that were not differentially expressed in our short-read data. We also identified several novel isoforms that are not included in the reference annotation. Our data collectively characterize the transcriptome of various neurodegenerative diseases and illuminate the mRNA isoform diversity.

• Type: RNASeq
• Archiver: European Genome-Phenome Archive (EGA)