Analysis of AMPA receptor subunit mRNA expression in control and ALS spinal cord

Virgo, L.; Samarasinghe, Sujith; Belleroche, Jacqueline de

doi:10.1097/00001756-199611040-00021

Cited by 42 publications

(20 citation statements)

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“…Extending these results, we found that the FUS C aggregates contain GRIA1 mRNA, a known FUS target encoding a glutamate receptor that was determined to be altered in ALS patient neural tissues (Supplemental Fig. 5; Virgo et al 1996;Petri et al 2004;Udagawa et al 2015). However, FISH with probes for IGFBP3 and NF-H mRNAs provided evidence that these mRNAs did not colocalize with the FUS C aggregates (Supplemental Fig.…”

Section: Mecp2 Mrna Colocalizes With Fus C In Cytoplasmic Aggregatesmentioning

confidence: 54%

ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ALS mutations in FUS might impact target gene expression, we examined the effects of several FUS derivatives harboring ALS mutations, such as R521C (FUS C ), on MECP2 expression in transfected human U87 cells. Strikingly, FUS C and other mutants not only altered MECP2 alternative splicing but also markedly increased mRNA abundance, which we show resulted from sharply elevated stability. Paradoxically, however, MeCP2 protein levels were significantly reduced in cells expressing ALS mutant derivatives. Providing a parsimonious explanation for these results, biochemical fractionation and in vivo localization studies revealed that MECP2 mRNA colocalized with cytoplasmic FUS C in insoluble aggregates, which are characteristic of ALS mutant proteins. Together, our results establish that ALS mutations in FUS can strongly impact target gene expression, reflecting a dominant effect of FUS-containing aggregates.

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Section: Mecp2 Mrna Colocalizes With Fus C In Cytoplasmic Aggregatesmentioning

confidence: 54%

ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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“…Previous studies with in situ hybridization have reported that human motoneurons either expressed (Tomiyama et al 1996;Virgo et al 1996) or did not express (Williams et al 1997) GluR2 mRNA. Our results revealed that GluR2 mRNA shared the vast majority (77.8%) among AMPA receptor subunits.…”

Section: Discussionmentioning

confidence: 94%

Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS

Kawahara

Kwak

Sun

et al. 2003

Journal of Neurochemistry

112

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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 Ca 2+ -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 receptormediated 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.

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“…GluR3-and GluR4-immunoreactive puncta were densely distributed throughout the ventral horn and laminas III-VI, with much weaker labeling in laminas I and II, although a few strongly labeled puncta were seen in this region, particularly in lamina I. It has been reported that motoneurons express GluR1 (PellegriniGiampietro et al, 1994;Virgo et al, 1996;Temkin et al, 1997;Williams et al, 1997;Bar-Peled et al, 1999;Shibata et al, 1999) or lack GluR2 subunits (Williams et al, 1997;Bar-Peled et al, 1999;Del Caño et al, 1999;Shaw et al, 1999). Our results do not support these suggestions, because we found that in lamina IX, there was virtually no punctate staining for GluR1, whereas GluR2 was expressed at virtually all puncta that contained any of the AMPA subunits (see below).…”

Section: Laminar Distribution Of Ampa Subunitsmentioning

confidence: 90%

Widespread Expression of the AMPA Receptor GluR2 Subunit at Glutamatergic Synapses in the Rat Spinal Cord and Phosphorylation of GluR1 in Response to Noxious Stimulation Revealed with an Antigen-Unmasking Method

Nagy¹,

Al-Ayyan²,

Andrew³

et al. 2004

J. Neurosci.

112

154

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Glutamate, the principal excitatory neurotransmitter in the spinal cord, acts primarily through AMPA receptors. Although all four AMPA subunits are expressed by spinal neurons, we know little about their distribution at glutamatergic synapses. We used an antigenunmasking technique to reveal the synaptic distribution of glutamate receptor (GluR) 1-4 subunits with confocal microscopy. After pepsin treatment, punctate staining was seen with antibodies against each subunit: GluR2-immunoreactive puncta were distributed throughout the gray matter, whereas GluR1-immunoreactive puncta were restricted to the dorsal horn and were most numerous in laminas I-II. Punctate staining for GluR3 and GluR4 was found in all laminas but was weak in superficial dorsal horn. Colocalization studies showed that GluR2 was present at virtually all (98%) puncta that were GluR1, GluR3, or GluR4 immunoreactive and that most (Ͼ90%) immunoreactive puncta in laminas IV, V, and IX showed GluR2, GluR3, and GluR4 immunoreactivity.Evidence that these puncta represented synaptic receptors was obtained with electron microscopy and by examining the association of GluR2-and GluR1-immunoreactive puncta with glutamatergic boutons (identified with vesicular glutamate transporters or markers for unmyelinated afferents). The great majority (96%) of these boutons were associated with GluR2-immunoreactive puncta. Our findings suggest that GluR2 is almost universally present at AMPA-containing synapses, whereas GluR1 is preferentially associated with primary afferent terminals.We also found a substantial, rapid increase in staining for synaptic GluR1 subunits phosphorylated on the S845 residue in the ipsilateral dorsal horn after peripheral noxious stimulation. This finding demonstrates plastic changes, presumably contributing to central sensitization, at the synaptic level.

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Analysis of AMPA receptor subunit mRNA expression in control and ALS spinal cord

Cited by 42 publications

References 0 publications

ALS mutations in TLS/FUS disrupt target gene expression

ALS mutations in TLS/FUS disrupt target gene expression

Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS

Widespread Expression of the AMPA Receptor GluR2 Subunit at Glutamatergic Synapses in the Rat Spinal Cord and Phosphorylation of GluR1 in Response to Noxious Stimulation Revealed with an Antigen-Unmasking Method

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