RNA Editing by ADAR Adenosine Deaminases in Cell Models of Cag Repeat Expansion Diseases: A Significant Effect of Differentiation from Stem Cells into Brain Organoids in Absence of a Substantial Influence of CAG Repeats on the Level of Editing

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Abstract

The expansion of CAG repeats in certain genes is a known cause of several neurodegenerative diseases, but the exact mechanism behind this is not yet fully understood. It is believed that double-stranded RNA regions formed by CAG repeats could be harmful to the cell. This study aimed to test the hypothesis that these RNA regions might potentially interfere with ADAR RNA editing enzymes, leading to reduced A→I editing of RNA and activation of the interferon response. We studied induced pluripotent stem cells (iPSCs) derived from patients with Huntington’s disease or ataxia type 17, as well as midbrain organoids developed from these cells. A targeted panel for next-generation sequencing was used to assess editing in specific RNA regions. The differentiation of iPSCs into brain organoids led to an increase in ADAR2 gene expression and a decrease in the expression of RNA editing inhibitor proteins. Consequently, there was an increase in the editing of specific ADAR2 substrates, allowing for the identification of differential substrates of ADAR isoforms. However, a comparison of pathology and control groups did not show differences in editing levels among iPSCs. Additionally, brain organoids with 42-46 CAG repeats did not exhibit global changes. On the other hand, brain organoids with the highest number of CAG repeats in the huntingtin gene (76) showed a significant decrease in the level of RNA editing of specific transcripts, potentially involving ADAR1. Notably, editing of the long non-coding RNA PWAR5 was nearly absent in this sample. In summary, the study found that in most cultures with repeat expansion, the hypothesized effect on RNA editing was not confirmed.

About the authors

V. V. Kudriavskii

Pirogov Russian National Research Medical University; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Author for correspondence.
Email: wkudriavskii@gmail.com
Russian Federation, 117997 Moscow; 119435 Moscow

A. O. Goncharov

Pirogov Russian National Research Medical University; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 117997 Moscow; 119435 Moscow

A. V. Eremeev

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 119435 Moscow

E. S. Ruchko

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 119435 Moscow

V. A. Veselovsky

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 119435 Moscow

K. M. Klimina

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 119435 Moscow

A. N. Bogomazova

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 119435 Moscow

M. A. Lagarkova

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: wkudriavskii@gmail.com
Russian Federation, 119435 Moscow

S. A. Moshkovskii

Pirogov Russian National Research Medical University; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: moshrffi@gmail.com
Russian Federation, 117997 Moscow; 119435 Moscow

А. А. Kliuchnikova

Pirogov Russian National Research Medical University; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency; Institute of Biomedical Chemistry

Email: wkudriavskii@gmail.com
Russian Federation, 117997 Moscow; 119435 Moscow; 119121 Moscow

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