Differential transcript usage in the Parkinson ’s disease brain

by Fiona Dick, Gonzalo S. Nido, Guido Werner Alves, Ole-Bj ørn Tysnes, Gry Hilde Nilsen, Christian Dölle, Charalampos Tzoulis Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcript-count based approaches, implemented in the DRIMSeq and DEXSeq tools. Multiple PD-associated DTU events were d etected in each cohort, of which 23 DTU events in 19 genes replicated across both patient cohorts. For several of these, includingTHEM5,SLC16A1 andBCHE, DTU was predicted to have substantial functional consequences, such as altered subcellular localization or switching to non-protein coding isoforms. Furthermore, genes with PD-associated DTU were enriched in functional pathways previously linked to PD, including reactive oxygen species generation and protein homeostasis. Importantly, the vast majority of genes exhibiting DTU were not differentially expressed at the gene-level and were therefore not identified by conventional differential gene expression analysis. Our findings provide the first insight into the DTU landscape of PD and identify novel disease-assoc...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research