Alzheimer’s disease pathogenetic progression is associated with changes in regulated retained introns and editing of circular RNAs

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Alvaro Gonzalo Hernandez¹  Giorgi Margvelani²  Sandra C. Miranda Sardón²  Karol Andrea Arizaca Maquera²  Samantha Hart²  Stefan Stamm²  Pierre de la Grange³  Noémie Robil³  Justin Ralph Welden⁴  Peter T. Nelson⁵ 

[1] DNA Services Facility, University of Illinois, Urbana, IL, United States;Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States;GenoSplice, Paris, France;Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States;Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States;Alzheimer’s Disease Research Center and Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, United States;

关键词: Alzheimer;    Braak stage;    circular RNAs;    alternative splicing;    gene expression;    retained intron;   

DOI  :  10.3389/fnmol.2023.1141079

 received in 2023-01-09, accepted in 2023-02-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe molecular changes leading to Alzheimer’s disease (AD) progression are poorly understood. A decisive factor in the disease occurs when neurofibrillary tangles (NFT) composed of microtubule associated protein tau (MAPT) form in the entorhinal cortex and then spread throughout the brain.MethodsWe therefore determined mRNA and circular RNA changes during AD progression, comparing Braak NFT stages I-VI. Total RNA was isolated from human brain (entorhinal and frontotemporal cortex). Poly(A)+ RNA was subjected to Nanopore sequencing, and total RNA was analyzed by standard Illumina sequencing. Circular RNAs were sequenced from RNase R treated and rRNA depleted total RNA. The sequences were analyzed using different bioinformatic tools, and expression constructs for circRNAs were analyzed in transfection experiments.ResultsWe detected 11,873 circRNAs of which 276 correlated with Braak NFT stages. Adenosine to inosine RNA editing increased about threefold in circRNAs during AD progression. Importantly, this correlation cannot be detected with mRNAs. CircMAN2A1 expression correlated with AD progression and transfection experiments indicated that RNA editing promoted its translation using start codons out of frame with linear mRNAs, which generates novel proteins.DiscussionThus, we identified novel regulated retained introns that correlate with NFT Braak stages and provide evidence for a role of translated circRNAs in AD development.

【 授权许可】

Unknown   
Copyright © 2023 Arizaca Maquera, Welden, Margvelani, Miranda Sardón, Hart, Robil, Hernandez, de la Grange, Nelson and Stamm.