Atlas of RNA editing events affecting protein expression in aged and Alzheimer\u2019s disease human brain tissue

Yiyi Ma,Charles C White,Xue Wang,Nilüfer Ertekin-Taner,Aĺlan I Levey ,Bin Zhang,David A Bennett,Nicholas T Seyfried,Duc Duong ,Hans-Ulrich Klein,Jishu Xu,Minghui Wang,Maotian Zhou,Cristin Mccabe,James J Lah,Daniel Felsky,Julie A Schneider ,Benjamin A Logsdon,Eric B Dammer,Mariet Allen,Thomas S Wingo,Philip L De Jager

doi:10.1038/s41467-021-27204-9

Abstract

RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer’s disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing.

Highlights

RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template
We have identified 112,779 frequent A-to-I RNA editing events, which are defined as those events with frequency ≥10%, across the ten datasets, and 58,761 (52%) of them are not reported before (Fig. 2a)
We found no change in ADAR1 expression, but there is lower expression of ADAR2 (P = 0.01) and higher expression of ADAR3 in Alzheimer’s disease (AD) cases (P = 0.01), while mild cognitive impairment (MCI) subjects are in the middle and the cognitively nonimpaired controls have the highest expression of ADAR2 and lowest expression of ADAR3, a potential RNA editing inhibitor[4]

Summary

Introduction

RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. A recent RNA sequencing (RNA-seq) study of human hippocampus samples showed significantly higher gene expression in six Alzheimer’s disease (AD) cases compared to six normal controls for ADAR3, but not ADAR1 or ADAR26. AD patients have been reported to have significantly lower levels of RNA editing at 14 re-coding sites in 11 genes, where the editing process changes the amino acid sequence of the targets[6]. Half of these sites were discovered previously with targeted sequencing measurements in fewer than 30 AD cases and controls[7]

Methods

Results

Conclusion