AMPA Receptor Current Density, Not Desensitization, Predicts Selective Motoneuron Vulnerability

Vandenberghe, Wim; Ihle, Eva C.; Patneau, Doris K.; Robberecht, Wim; Brorson, James R.

doi:10.1523/jneurosci.20-19-07158.2000

Cited by 74 publications

(49 citation statements)

References 53 publications

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“…AMPAR changes have been demonstrated as a contributor in both in vitro and in vivo models of SOD1‐ALS (Van Damme et al, 2007), in vitro studies of C9orf72‐ALS (Donnelly et al, 2013), postmortem studies of sporadic ALS (Kwak, Hideyama, Yamashita, & Aizawa, 2010), and cell‐autonomous studies of FUS‐ALS (Udagawa et al, 2015). Motor neurons are known to be especially vulnerable to AMPA‐mediated excitotoxicity due to an unusually high density of Ca 2+ ‐permeable AMPA receptors and low calcium buffering ability (Palecek, Lips, & Keller, 1999; Vandenberghe et al 2000). Furthermore, neighboring astrocytes are known to be key regulators of these AMPA receptors (Beattie, 2002; Van Damme et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

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Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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“…The double assaults by mitochondrial dysfunction and glutamate induced excitotoxicity may explain the selectivity of motoneuron death in ALS. Motoneurons display a higher AMPA receptor density on their surface than other neurons (Vandenberghe et al 2000) and are particularly susceptible to mitochondrial calcium overload when exposed to AMPA (Carriedo et al 2000). Not surprisingly, chronic partial disruption of mitochondrial function causes motoneuron death and this death can be inhibited by applying excitatory amino acid blockers (Kaal et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Jung

Higgins

2002

Journal of Neurochemistry

183

111

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.

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“…MNs were isolated and cultured from rat embryos according to previously described methods (25) with some modifications. In brief, a ventral portion of spinal cord was dissected from 14-day-old Holtzmann rat embryos, and MNs were purified by centrifugation on a 6.5% metrizamide (Sigma) cushion.…”

Section: Methodsmentioning

confidence: 99%

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghadge

Slusher

Bodner

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

114

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Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and Ϸ20% of these cases of familial ALS (FALS) are caused by mutations of copper͞zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.A myotrophic lateral sclerosis (ALS) is a progressive and fatal degeneration of motor neurons (MNs) in the spinal cord and cerebral cortex. About 10% of ALS cases are inherited in an autosomal dominant fashion, and Ϸ20% of these cases of familial ALS (FALS) are caused by a mutation in copper͞zinc superoxide dismutase type 1 (SOD1) (1). Mice and rats that carry mutant (MT) SOD1 as a transgene manifest a progressive MN degeneration similar to that in patients with ALS (2-4). Several lines of evidence suggest that glutamate excitotoxicity is a pathogenic mechanism in both sporadic .N-acetylaspartylglutamate (NAAG) is one of the most abundant peptides in the mammalian central and peripheral nervous system (14), is present in neuronal vesicles, is released from neurons in a calcium-dependent manner, and functions as a high-affinity agonist at the group II metabotropic glutamate receptor subtype 3 (mGluR3). Activation of mGluR3 by NAAG has been shown to inhibit glutamate release (15), increase release of transforming growth factor ␤ (TGF␤) from glial cells, and provide neuroprotection (16). NAAG is hydrolyzed to N-acetylaspartate and glutamate by glutamate carboxypeptidase II (GCPII) (EC 3.4.17.21; also termed N-acetylated-␣-linked acidic dipeptidase or NAALADase; ref. 17), an enzyme localized on the plasma membrane of glial cells with its catalytic region facing the synapse (18). Therefore, inhibition of GCPII would be expected to provide neuroprotection by means of both decreasing glutamate and increasing NAAG (19).We hypothesized that GCPII inhibition would protect MNs expressing MT SOD1 from cell death, as well as ameliorate the MN degeneration seen in FALS transgenic mouse. For in vitro studies, we used 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent and selective GCPII inhibitor (K i ϭ 0.2 nM; ref. 20) that has been shown to selectively reduce ischemic glutamate and provide neuroprotection in cell culture and animal models of ischemia (19), diabetic neuropathy (21), and drug abuse (22, 23). For the animal studies, we used a recently discovered thiol-based GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA) (24). Unlike 2-PMPA, 2-MPPA is o...

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AMPA Receptor Current Density, Not Desensitization, Predicts Selective Motoneuron Vulnerability

Cited by 74 publications

References 53 publications

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

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