Abstract
Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca2+ influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and is characterized by progressive loss of both upper and lower motor neurons
In order to assess whether the expression of GluA2Q resulting from adenosine deaminase acting on RNA 2 (ADAR2) downregulation is a cause of neuronal death, we developed a conditional ADAR2 knockout mouse line using a
ADAR2 knockout mice (AR2) mice exhibited progressive declines in motor observed in various neurological diseases, including Alzheimer0 s disease, traumatic brain injury, function, in parallel with progressive loss of ADAR2-deficient motor neurons
Summary
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and is characterized by progressive loss of both upper and lower motor neurons. Varied disease mechanisms leading to motor neuron death in ALS include RNA misprocessing (metabolism), protein misfolding, and excitotoxicity [2,3]. In sporadic ALS and some familial ALS, including C9ORF72- and TARDBP-associated ALS, loss of transactive response element DNA/RNA binding protein 43 (TDP-43) in the nucleus and abnormal. TDP-43 pathology, including insoluble, hyperphosphorylated, and in the motor neurons of patients with ALS [13,18]. AR2 mice) demonstrated that insufficient ADAR2 expression induced motor neuron death via an mislocalization. TDP-43 or other patterns of TDPTDP-43 pathology in sporadic ALS is similar to that observed in AR2 mice [18,19,20,21,22]. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; TDP-43 = transactive response DNA-binding protein; MNs = motor neurons
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