Exploring Emotional Attachment to Socially Assistive Robots: A Qualitative Study Among Older Adults.

With the potential for long-term functional restoration via DNA- or RNA-based therapeutics, gene therapy has become a viable alternative to traditional pharmacotherapy for central nervous system (CNS) diseases []. Adenosine-to-inosine (A-to-I) editing is one of the most common post-transcriptional RNA modifications in the CNS and is crucial for healthy brain development and function. It is performed by adenosine deaminases acting on RNA (ADAR) [, ]. In double-stranded RNA (dsRNA), ADAR1 and ADAR2 convert adenosine to inosine. This mechanism recodes ion channels and neurotransmitter receptors, controls splicing and microRNA (miRNA) targeting, and stops unwanted immune activation by designating endogenous dsRNA as “self” [–]. In contrast, ADAR3 may act as a competitive inhibitor in the brain and lacks catalytic activity []. The editing of the glutamate receptor subunit GluA2 (also called GluR2) by ADAR2 represents a key paradigm in the area. In the ion channel pore, editing changes a glutamine (Q) codon to an arginine (R) codon, making α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors impermeable to Ca and preventing excitotoxicity []. A wide range of CNS disorders, including neurodegenerative diseases (Alzheimer’s disease [AD], Parkinson’s disease [PD], amyotrophic lateral sclerosis [ALS]), neuropsychiatric conditions (schizophrenia, bipolar disorder [BPD]), autoimmune encephalopathy (Aicardi–Goutières syndrome [AGS]), and brain tumors, are increasingly associated with loss of this editing event, or dysregulation of ADAR1-mediated immune surveillance [, ]. Notably, primate-specific Alu (a family of short, interspersed, repetitive DNA elements) elements account for more than 99% of editing sites, in which inverted repeats provide the dsRNA structures required for ADAR binding []. This study examines a crucial open question: In many CNS disorders, does altered ADAR-mediated RNA editing function as a major driver of pathogenesis, a compensatory reaction, or a context-dependent modulator (Fig. )? First, we provide an overview of the basic processes of ADAR enzymes and their functions in synaptic plasticity and neurodevelopment. The data connecting ADAR dysregulation to certain neurological and neuropsychiatric disorders, as well as CNS malignancies, are then methodically assessed. Lastly, we analyze new treatment approaches that use or restore ADAR activity, such as small-molecule modulators and site-directed RNA editing (SDRE) tools, and we review the main obstacles to clinical translation, including delivery, specificity, and safety.