Glutamate receptors: RNA editing and death of motor neurons

@article{Kawahara2004GlutamateRR,
  title={Glutamate receptors: RNA editing and death of motor neurons},
  author={Yukio Kawahara and Kyoko Ito and Hui Sun and Hitoshi Aizawa and Ichiro Kanazawa and Shin Kwak},
  journal={Nature},
  year={2004},
  volume={427},
  pages={801-801}
}
The aetiology of sporadic amyotrophic lateral sclerosis (ALS), a fatal paralytic disease, is largely unknown. Here we show that there is 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. This failure to swap an arginine for a glutamine residue at a crucial site in the subunit, which occurs normally in the affected brain areas of patients with other neurodegenerative diseases, will… 
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509 Citations
Highly Influential Citations
14
Background Citations
187
Methods Citations
7
Results Citations
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509 Citations

Edited GluR2, a gatekeeper for motor neurone survival?
TLDR
It is suggested that edited AMPA glutamate (GluR2) receptor subunits serve as gatekeepers for motor neurone survival and are linked with sporadic ALS.
Underediting of GluR2 mRNA, a neuronal death inducing molecular change in sporadic ALS, does not occur in motor neurons in ALS1 or SBMA
Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons
The role of RNA processing in the pathogenesis of motor neuron degeneration
TLDR
This work has shown that motor neuron degeneration can result from mutation in genes that encode factors important for ribonucleoprotein biogenesis and RNA processing, including splicing regulation, transcript stabilisation, translational repression and localisation of mRNA.
The role of AMPA receptor-mediated excitotoxicity in ALS: Is deficient RNA editing to blame?
Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis
TLDR
GluR2 underediting occurs in a disease specific and region selective manner and is likely that the molecular mechanism underlying the deficiency in RNA editing is a reduction in the activity of ADAR2, a double- strand RNA specific deaminase.
Investigating RNA editing in the pathogenesis of Amyotrophic Lateral Sclerosis
TLDR
It was demonstrated that GLUR2 was fully edited in the MNs of ALS/C9ORF72- positive, ALS/ c9ORf72-negative cases and controls, and full editing of GLur2 in dissected motor neurons isolated by LCM was confirmed.
The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice
TLDR
It is shown that orally administered perampanel, a selective, non-competitive AMPA receptor antagonist significantly prevented the progression of the ALS phenotype and normalized the TDP-43 pathology-associated death of motor neurons in the AR2 mice.
Exploration of the Pathogenesis of Amyotrophic Lateral Sclerosis from the Perspective of Motor Neuron TDP-43 Protein Expression and ADAR2 Activity
TLDR
Upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 vector that enables gene delivery to a wide array of central neurons after peripheral administration effectively prevented progressive motor dysfunction and rescued the motor neurons from death by normalizing TDP-43 expression.
7 Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis
TLDR
This chapter concentrates on the interplay between altered electrophysiological properties and molecular events in the time leading up to overt symptom onset of ALS.
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RNA editing in brain controls a determinant of ion flow in glutamate-gated channels
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