The possible effect of off-target activity by endogenous ADAR on misfolded proteins:

Adenosine-to-inosine (A-to-I) RNA editing by the adenosine deaminase that acts on RNA (ADAR) enzymes is a common RNA modification, that prevents false activation of the innate immune system and diversifies the transcriptome. Most A-to-I editing sites are located within mobile elements in non-coding parts of the genome. In addition, there is a number of `recoding` sites at which A-to-I editing results in non-synonymous substitutions in protein-coding sequences. One of the problems of the RNA editing process is the off-target activity. Off-target activity of the RNA editing in protein coding regions can lead to accumulation of misfolded proteins and eventually to aggregation, a key contributor to neurodegenerative diseases. In this study we are trying to show the connection between off-target activity by the endogenous ADAR in coding regions and misfolded proteins that eventually will aggregate. So far, we compared data with knockout of ADAR or with overexpression of ADAR against controls. We found that in some of these studies there are differences in editing levels in coding regions. Our results demonstrates that there is promise in further conducting the mentioned research directions in order to confirm our hypothesis.