Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model

Tateno, Minako; Sadakata, Hisako; Tanaka, Mika; Itohara, Shigeyoshi; Shin, Ryong Moon; Miura, Masami; Masuda, Masao; Aosaki, Toshihiko; Urushitani, Makoto; Misawa, Hidemi; Takahashi, Ryōsuke

doi:10.1093/hmg/ddh246

Cited by 133 publications

(94 citation statements)

References 46 publications

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“…Furthermore, SOD1 mutants inactivate the highaffinity glutamate transporter GLT1, which is the predominant isoform involved in keeping extracellular glutamate at nontoxic concentrations (26). Crossbreeding of the hSOD1G93A transgenic mice with chat-GluR-B mice, which show reduced Ca 2ϩ -permeability of AMPA channels, delays disease onset and reduces mortality in double-transgenics (27), whereas crossbreeding of the hSOD1G93A transgenic mice with GluR-B(N) mice accelerates disease progression, aggravates severity of motor decline, and decreases survival. Glutamate carboxypeptidase II inhibition protects motoneurons from death in familial ALS, further confirming that glutamate plays a key role in mediating motoneuron death (28).…”

Section: Discussionmentioning

confidence: 99%

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

Kuner

Groom²,

Bresink³

et al. 2005

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

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Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu 2؉ ͞Zn 2؉ superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-␣-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca 2؉ permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca 2؉ influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.amyotrophic lateral sclerosis ͉ Ca 2ϩ permeable ion channels ͉ GluR-B gene

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Section: Discussionmentioning

confidence: 99%

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

Kuner

Groom²,

Bresink³

et al. 2005

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

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“…Currently, the best animal models of ALS are provided by rodents harboring mutant forms of the enzyme Cu, Zn superoxide dismutase (SOD1), which are associated with familial ALS in humans. Solidifying the role of Ca-AMPA channels in in vivo models of ALS, recent studies indicate that the rate of progression of MN loss in SOD1 mutant mice varies bidirectionally with the level of expression of these channels (Kuner et al, 2005;Tateno et al, 2004;Van Damme et al, 2005). In addition, Ca-AMPA channels appear to contribute to MN loss in a distinct form of familial ALS, not linked to SOD1 (Lai et al, 2006) and a Ca-AMPA channel blocker was found to be protective in a model of virus induced MN degeneration (Darman et al, 2004).…”

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confidence: 99%

Intrathecal infusion of a Ca2+-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS

Yin

Tang

Weiss

2007

Experimental Neurology

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Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca 2+ permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca 2+ overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 d) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham treated G93A animals, 30 day NAS infusions (starting at 67 ±2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes.

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“…183,184 Then, crossbreeding SOD1 G93A mice with ChAT-GluR2 overexpressing mice, for which AMPA Ca 2+ -permeability is significantly reduced in cholinergic neurons, was shown to delay disease onset (∼19%) and mortality (∼14%) and to alleviate SOD1 protein misfolding. 185 In contrast, crossbreeding of SOD1 G93A mice with GluR2 knockout mice was found to accelerate disease progression and animal death (∼15% for both). 186 As GluR2 mRNA levels are unchanged over the course of the disease in SOD1 G93A mice, 187 but GluR2 protein is specifically decreased in spinal MNs before symptom onset, the beneficial effects of GluR2 overexpression may rely on both a global reduction in Ca 2+ influx through AMPA GluR and on a compensatory GluR2 protein translation defect or instability.…”

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

confidence: 99%

“…• Increased survival (SOD1 G93A mice) • AMPA antagonist (+10%) 183,184 • GluR2 overexpression (+14%) 185 • No GluR2 mRNA/protein levels difference 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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Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model

Cited by 133 publications

References 46 publications

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

Intrathecal infusion of a Ca2+-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS

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

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