The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice

  title={The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice},
  author={Megumi Akamatsu and Takenari Yamashita and Naoki Hirose and Sayaka Teramoto and Shin Kwak},
  journal={Scientific Reports},
Both TDP-43 pathology and failure of RNA editing of AMPA receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS). AR2 mice, in which an RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is conditionally knocked out in the motor neurons, exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons through a Ca2+-permeable AMPA receptor… 
Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis
The evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur inALS, and normalization of disrupted intracellular environments resulting from ADAR1 downregulation may be a therapeutic target for ALS.
Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model
A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons.
Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons
It was shown that nucleoporins that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice, suggesting that calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2-mediated cell death signals may be a therapeutic strategy for ALS.
Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity
It is revealed that glial glutamate transporter dysfunction is sufficient to cause motor neuronal death in vivo, and normalization of NPC function could be a novel therapeutic strategy for neurodegenerative disorders in which AMPA receptor-mediated excitotoxicity is a contributory factor.
Glutamic acid metabolism alterations, causes and consequences in ALS
A connection between Glutamate metabolism disorders and TDP-43 proteinopathy, two pathological mechanisms of primary importance in ALS are shown for the first time.
RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases
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
A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability
This study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where un edited GLUA 2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed.
ALSUntangled 48: Perampanel (Fycompa)
  • R. Bedlack
  • Biology
    Amyotrophic lateral sclerosis & frontotemporal degeneration
  • 2019
The demonstrated ability of perampanel to treat most types of seizures, which has been replicated in multiple clinical trials, strongly suggests it has an inhibitory effect on neurotransmission.


Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons
This work explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno‐associated virus serotype 9 (AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration and rescued the motor neurons of AR2 mice from death by normalizing TDP‐43 expression.
Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2
GluR2 Q/R site editing causes AMPA receptor-mediated death of motor neurons in genetically modified mice and shows a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons.
When Does ALS Start? ADAR2–GluA2 Hypothesis for the Etiology of Sporadic ALS
It is hypothesized that a progressive downregulation of ADAR2 activity plays a critical role in the pathogenesis of sporadic ALS and that the pathological process commences when motor neurons express unedited GluA2.
A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.
Activation of calpain by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-cleaved TDP-43 fragments and causes mislocalization in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology.
SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments
The SOD1 and TDP-43 animal models created to date are summarised, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic.
Excitotoxicity and ALS: What is unique about the AMPA receptors expressed on spinal motor neurons?
  • Y. Kawahara, S. Kwak
  • Biology
    Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases
  • 2005
This review focuses on recent progress on the molecular dynamics of AMPA receptors and discusses the pathophysiology of selective motor neuron death mediated by AM PA receptors in individuals affected with sporadic ALS.
Glutamate receptors: RNA editing and death of motor neurons
A defect in the editing of the messenger RNA encoding the GluR2 subunit of glutamate AMPA receptors in the spinal motor neurons of individuals affected by ALS will interfere with the correct functioning of the glutamate receptors and may be a contributory cause of neuronal death in ALS patients.
TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2
The results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology, which is found to be found in spinal motor neurons of patients with sporadic ALS.