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Published on: November 12, 2019
Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS
Yukio Kawahara1, Shin Kwak, Hui Sun
1Department of Neurology, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo, Japan.
Abstract:
AMPA receptor-mediated neurotoxicity is currently the most plausible hypothesis for the etiology of amyotrophic lateral sclerosis (ALS). The mechanism initiating this type of neuronal death is believed to be exaggerated Ca2+-influx through AMPA receptors, which is critically determined by the presence or absence of the glutamate receptor subunit 2 (GluR2) in the assembly. We have provided the first quantitative measurements of the expression profile of AMPA receptor subunits mRNAs in human single neurons by means of quantitative RT-PCR with a laser microdissector. Among the AMPA subunits, GluR2 shared the vast majority throughout the neuronal subsets and tissues examined. Furthermore, both the expression level and the proportion of GluR2 mRNA in motoneurons were the lowest among all neuronal subsets examined, whereas those in motoneurons of ALS did not differ from the control group, implying that selective reduction of the GluR2 subunit cannot be a mechanism of AMPA receptor-mediated neurotoxicity in ALS. However, the low relative abundance of GluR2 might provide spinal motoneurons with conditions that are easily affected by changes of AMPA receptor properties including deficient GluR2 mRNA editing in ALS.
Insights
Amyotrophic lateral sclerosis (ALS) may involve AMPA receptor neurotoxicity. Researchers found GluR2 mRNA levels in spinal motoneurons are low but not reduced in ALS, suggesting other factors may cause this neurodegenerative disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease.
- AMPA receptor-mediated neurotoxicity is a leading hypothesis for ALS etiology.
- Exaggerated calcium influx through AMPA receptors, dependent on GluR2 subunit presence, is the proposed mechanism.
Purpose of the Study:
- To quantitatively measure AMPA receptor subunit mRNA expression in human single neurons.
- To investigate the role of GluR2 subunit expression in motoneuron neurotoxicity in ALS.
Main Methods:
- Quantitative RT-PCR (Reverse Transcription Polymerase Chain Reaction) on single human neurons.
- Laser microdissection for precise cell isolation.
- Analysis of AMPA receptor subunit mRNA expression profiles.
Main Results:
- GluR2 mRNA was the most abundant AMPA subunit across neuronal types.
- Spinal motoneurons exhibited the lowest expression level and proportion of GluR2 mRNA.
- GluR2 mRNA levels in ALS motoneurons were comparable to control groups.
Conclusions:
- Selective reduction of GluR2 subunit is unlikely to cause ALS neurotoxicity.
- Low basal GluR2 expression in motoneurons may predispose them to excitotoxicity.
- Altered AMPA receptor properties, potentially including GluR2 mRNA editing, may contribute to ALS pathogenesis.
