GluR2 AMPA Receptor Subunit Expression in Motoneurons at Low and High Risk for Degeneration in Amyotrophic Lateral Sclerosis

Laslo, Peter; Lipski, Janusz; Nicholson, Louise; Miles, Gareth B.; Funk, Gregory D.

doi:10.1006/exnr.2001.7653

Cited by 50 publications

(33 citation statements)

References 62 publications

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“…The discrepancy is presumably due to the insensitivity of the in situ hybridization method on human materials. Indeed, the mRNA of all four GluR subunits was demonstrated in the rat spinal motoneurons with in situ hybridization (Furuyama et al 1993;Tö lle et al 1993;Grossman et al 1999;Laslo et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, patch-clamp electrophysiological measurements on dissociated rat spinal cord cultures demonstrated a two-to threefold higher AMPA receptor current density in motoneurons than in dorsal horn neurons ( Vandenberghe et al 2000a), reflecting relatively high AMPA receptor density in the rat spinal motoneurons. To resolve the above inconsistency, analysis of AMPA receptor subunits at a protein level is essential, but previous studies with immunohistochemistry either failed to detect GluR2 in human motoneurons or reported inconsistent results in rat and mouse motoneurons (Morrison et al 1998;Bar-Peled et al 1999;Laslo et al 2001).…”

Section: Discussionmentioning

confidence: 99%

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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

111

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

111

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“…184 Nevertheless, no difference in GluR2 mRNA and protein expression was observed between human ALS and control tissues, 155 or between resistant and vulnerable rat MNs. 188 Altogether these results suggest that reduced expression of GluR2 is not a crucial factor predisposing MNs to degeneration in ALS per se but that AMPA GluRs have a modulatory role worth further investigation, at least, in the mutant SOD1-linked familial form of ALS.…”

Section: Mn Glur Alteration In Als: Zoom In On Glur2 Loss and Editingmentioning

confidence: 87%

“…• MNs of ALS and control patients 155 • ALS resistant and vulnerable MNs 188 • Accelerated death (SOD1 G93A mice) • GluR2 KO (+15%) 186 • unedited GluR2 (+7%) 169 • GluR2 protein decrease (presymptomatic SOD1 G93A MNs) 184 • No GluR2 editing defect in:…”

Section: Pro Conmentioning

confidence: 99%

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Verche¹,

Ikiz²,

Jacquier³

et al. 2010

JRLCR

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Abstract:The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ∼20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca 2+ -mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca 2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

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“…In neurodegenerative diseases such as the bulbar form of amyotrophic lateral sclerosis (ALS), the nucleus hypoglossus is among the most vulnerable (Krieger et al 1994;Lips & Keller 1999;Laslo et al 2001). In ALS, pathological clonic muscle contractions often precede muscle paralysis.…”

Section: Rhythmic Electrical Discharges Are Necessary For Stereotypicmentioning

confidence: 99%

A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions

Cifra

Nani

Sharifullina

et al. 2009

Phil. Trans. R. Soc. B

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The brainstem nucleus hypoglossus contains motoneurons that provide the exclusive motor nerve supply to the tongue. In addition to voluntary tongue movements, tongue muscles rhythmically contract during a wide range of physiological activities, such as respiration, swallowing, chewing and sucking. Hypoglossal motoneurons are destroyed early in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease often associated with a deficit in the transport system of the neurotransmitter glutamate.The present study shows how periodic electrical discharges of motoneurons are mainly produced by a neuronal network that drives them into bursting mode via glutamatergic excitatory synapses. Burst activity is, however, modulated by the intrinsic properties of motoneurons that collectively synchronize their discharges via gap junctions to create 'group bursters'. When glial uptake of glutamate is blocked, a distinct form of pathological bursting spontaneously emerges and leads to motoneuron death. Conversely, H 2 O 2 -induced oxidative stress strongly increases motoneuron excitability without eliciting bursting. Riluzole (the only drug currently licensed for the treatment of ALS) suppresses bursting of hypoglossal motoneurons caused by blockage of glutamate uptake and limits motoneuron death. These findings highlight how different patterns of electrical oscillations of brainstem motoneurons underpin not only certain physiological activities, but also motoneuron death induced by glutamate transporter impairment.

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GluR2 AMPA Receptor Subunit Expression in Motoneurons at Low and High Risk for Degeneration in Amyotrophic Lateral Sclerosis

Cited by 50 publications

References 62 publications

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

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

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions

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