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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180
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Results Citations
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504 Citations

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Citation Type

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?
RNA processing defects associated with diseases of the motor neuron
TLDR
This review provides a summary of currently recognized RNA processing defects linked to human motor neuron diseases and suggests motor neurons are uniquely sensitive to perturbations in RNA processing pathways.
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.
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References

SHOWING 1-10 OF 10 REFERENCES
Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis
Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia
Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS
TLDR
The first quantitative measurements of the expression profile of AMPA receptor subunits mRNAs in human single neurons are provided by means of quantitative RT–PCR with a laser microdissector, showing that among the AMPA subunits, GluR2 shared the vast majority throughout the neuronal subsets and tissues examined.
Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis
TLDR
The decrement of GluR2 mRNA editing efficiency is unique to the ventral gray of ALS cases and may be closely linked to the etiology of ALS.
Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice
The arginine residue at position 586 of the GluR-B subunit renders heteromeric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptor channels impermeable to calcium.…
RNA editing in brain controls a determinant of ion flow in glutamate-gated channels
Neurological dysfunctions in mice expressing different levels of the Q/R site–unedited AMPAR subunit GluR–B
TLDR
Mouse mutants with targeted AMPA receptor GluR–B subunit alleles, functionally expressed at different levels and deficient in Q/R–site editing have mild to severe neurological dysfunctions, including epilepsy and deficits in dendritic architecture.
Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2
TLDR
It is concluded that this transcript is the physiologically most important substrate of ADAR2, as it specifies an ion channel determinant, the Q/R site, in AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor GluR-B pre-messenger RNA.
AMPA Receptor Tetramerization Is Mediated by Q/R Editing
Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain
TLDR
The results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell‐specific, manner and that the GluR2 Q/ R site editing is critically regulated by ADAR2 in human brain.