In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing.

Cell Reports
John R SinnamonGail Mandel

Abstract

Programmable RNA editing is gaining momentum as an approach to repair mutations, but its efficiency in repairing endogenous mutant RNA in complex tissue is unknown. Here we apply this approach to the brain and successfully repair a guanosine-to-adenosine mutation in methyl CpG binding protein 2 RNA that causes the neurodevelopmental disease Rett syndrome. Repair is mediated by hippocampal injections of juvenile Mecp2317G>A mice with an adeno-associated virus expressing the hyperactive catalytic domain of adenosine deaminase acting on RNA 2 and Mecp2 guide. After 1 month, 50% of Mecp2 RNA is recoded in three different hippocampal neuronal populations. MeCP2 protein localization to heterochromatin is restored in neurons to 50% of wild-type levels. Whole-transcriptome RNA analysis of one neuronal population indicates that the majority of off-target editing sites exhibit rates of 30% or less. This study demonstrates that programmable RNA editing can be utilized to repair mutations in mouse models of neurological disease.

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Citations

Sep 4, 2020·Journal of Neurochemistry·Thomas J TurnerGabriele Lignani
Dec 29, 2020·Critical Reviews in Biochemistry and Molecular Biology·Emily A ErdmannHeather A Hundley
Feb 9, 2021·Frontiers in Genetics·Katrina V GoodJuan Ausió
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Dec 5, 2020·ACS Central Science·Simone RauchBryan C Dickinson
Sep 28, 2021·RNA Biology·Hamid Mansouri Khosravi, Michael F Jantsch

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Methods Mentioned

BETA
deamination
laser capture micro-dissection
RNA-seq
transfection
confocal microscopy
exome sequencing
genotyping
restriction digest
PCR
dot blot

Key Resources (RRID) Mentioned

SCR_013672

Software Mentioned

GraphPad Prism
Bowtie
Bioedit
ImageJ
REDItoolDnaRna

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