RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases.

Takashi Hosaka,Hiroshi Tsuji,Shin Kwak

doi:10.3390/ijms222010958

Abstract

The conversion of adenosine to inosine in RNA editing (A-to-I RNA editing) is recognized as a critical post-transcriptional modification of RNA by adenosine deaminases acting on RNAs (ADARs). A-to-I RNA editing occurs predominantly in mammalian and human central nervous systems and can alter the function of translated proteins, including neurotransmitter receptors and ion channels; therefore, the role of dysregulated RNA editing in the pathogenesis of neurological diseases has been speculated. Specifically, the failure of A-to-I RNA editing at the glutamine/arginine (Q/R) site of the GluA2 subunit causes excessive permeability of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to Ca2+, inducing fatal status epilepticus and the neurodegeneration of motor neurons in mice. Therefore, an RNA editing deficiency at the Q/R site in GluA2 due to the downregulation of ADAR2 in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients suggests that Ca2+-permeable AMPA receptors and the dysregulation of RNA editing are suitable therapeutic targets for ALS. Gene therapy has recently emerged as a new therapeutic opportunity for many heretofore incurable diseases, and RNA editing dysregulation can be a target for gene therapy; therefore, we reviewed neurological diseases associated with dysregulated RNA editing and a new therapeutic approach targeting dysregulated RNA editing, especially one that is effective in ALS.

Highlights

Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease in the USA, is an adult-onset fatal motor neuron disease characterized by the degeneration of the upper and lower motor neurons, resulting in progressive muscular weakness and death due to respiratory failure [1]
As some recent excellent reviews have described the association of RNA editing with neurodegenerative diseases or current and promising gene therapies for neurodegeneration in general [41,42,43,44], we focused on ALSrelated excitotoxicity due to the dysfunction of glutamatergic signaling resulting from dysregulated RNA editing at the GluA2 Q/R site, which are promising future targets in amyotrophic lateral sclerosis (ALS) therapy
Malignant glioma is associated with a reduction in RNA editing at various A-to-I sites, including the isoleucine/methionine (I/M) site in gamma-aminobutyric acid type A receptor subunit alpha 3 (GABRA3) [78], five editing sites in cell division cycle 14 B (CDC14B) [79], the +9 site of miR-336, and the +6 site of miR-589-3p [80,81]. Another neurological disease associated with deficient RNA editing is brain ischemia, in which an aberrant Ca2+ influx through Q/R site-unedited GluA2 containing Ca2+permeable amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been suspected to play a crucial role in the neuronal death of CA1 pyramidal neurons in mice [82,83]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease in the USA, is an adult-onset fatal motor neuron disease characterized by the degeneration of the upper (cortical) and lower (spinal and brain stem) motor neurons, resulting in progressive muscular weakness and death due to respiratory failure [1]. EAAT1 to EAAT5, are known in the EAAT family: EAAT1 or GLAST is the major glutamate transporter and is primarily expressed in the Bergmann glial cells of the cerebellar cortex; EAAT2, or GLT-1, is responsible for more than 90% of glutamate uptake and is expressed primarily in the astrocytes of the cerebral cortex and hippocampus; EAAT3, or excitatory amino acid carrier 1 (EAAC1), is primarily expressed in the pre-synaptic neurons of the cerebral cortex and basal ganglia, while EAAT4 and EAAT5 are low-capacity glutamate transporters expressed in the postsynaptic dendrites of the Purkinje cells of the cerebellar cortex and the amacrine cells of the retina, respectively [6]. As some recent excellent reviews have described the association of RNA editing with neurodegenerative diseases or current and promising gene therapies for neurodegeneration in general [41,42,43,44], we focused on ALSrelated excitotoxicity due to the dysfunction of glutamatergic signaling resulting from dysregulated RNA editing at the GluA2 Q/R site, which are promising future targets in ALS therapy

RNA Editing and Neurological Diseases

Findings

Conclusions