Abstract
Adenosine to inosine (A-to-I) RNA editing, catalyzed by the ADAR enzyme family, acts on dsRNA structures within pre-mRNA molecules. Editing of the coding part of the mRNA may lead to recoding, amino acid substitution in the resulting protein, possibly modifying its biochemical and biophysical properties. Altered RNA editing patterns have been observed in various neurological pathologies. Here, we present a comprehensive study of recoding by RNA editing in Alzheimer's disease (AD), the most common cause of irreversible dementia. We have used a targeted resequencing approach supplemented by a microfluidic-based high-throughput PCR coupled with next-generation sequencing to accurately quantify A-to-I RNA editing levels in a preselected set of target sites, mostly located within the coding sequence of synaptic genes. Overall, editing levels decreased in AD patients' brain tissues, mainly in the hippocampus and to a lesser degree in the temporal and frontal lobes. Differential RNA editing levels were observed in 35 target sites within 22 genes. These results may shed light on a possible association between the neurodegenerative processes typical for AD and deficient RNA editing.
| Original language | English |
|---|---|
| Pages (from-to) | 290-302 |
| Number of pages | 13 |
| Journal | RNA |
| Volume | 22 |
| Issue number | 2 |
| Early online date | 11 Dec 2015 |
| DOIs | |
| State | Published - Feb 2016 |
Bibliographical note
Publisher Copyright:© 2016 Khermesh et al.
Funding
The authors thank Gideon Rechavi, Jin Billy Li, Rui Zhang, Gokul Ramaswami, and Itzhak Haviv for their assistance with the experimental system. We also thank Italia Aiello and Francesca Mastropasqua for support with brain tissues and Graziano Pesole for helpful suggestions. A special thanks is addressed to the following brain banks: Netherlands Brain Bank (NBB), Brain and Tissue Bank for Developmental Disorders (NICHD), London Neurodegenerative Diseases Brain Bank (LNDBB), and Parkinson’s UK Brain Bank (PUKBB) for providing all tissues used in this study. This research was supported by a grant from the Ministry of Science, Technology and Space, Israel and the Ministry of Foreign Affairs, Italy to E.E. and E.P. Additional support came from the European Research Council (grant no. 311257), the I-CORE Program of the Planning and Budgeting Committee, and the Israel Science Foundation (grant nos. 41/11 and 1796/12; 1380/14 [E.Y.L.] and 379/12 [E.E.]). Additional support for E.Y.L. was provided by the Ministry of Science and Technology, Israel and the Japan Science and Technology Agency (JST), Japan (grant no.10765-3).
| Funders | Funder number |
|---|---|
| Brain and Tissue Bank for Developmental Disorders | |
| London Neurodegenerative Diseases Brain Bank | |
| Parkinson’s UK Brain Bank | |
| Eunice Kennedy Shriver National Institute of Child Health and Human Development | |
| Nederlandse Hersenbank | |
| European Commission | 311257 |
| Ministry of Science, Technology and Space | |
| Japan Science and Technology Agency | |
| Ministry of Foreign Affairs | |
| Israel Science Foundation | 41/11, 379/12, 1796/12, 1380/14 |
| Israeli Centers for Research Excellence | |
| Ministry of science and technology, Israel |
Keywords
- Alzheimer disease
- Epigenetics
- RNA editing
- Targeted resequencing