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

Ghadge, Ghanashyam D.; Slusher, Barbara S.; Bodner, Amos; Canto, Mauro Dal; Wozniak, Krystyna M.; Thomas, Ajit G.; Rojas, Camilo; Tsukamoto, Takashi; Majer, Pavel; Miller, Richard J.; Monti, Anna Liza; Roos, Raymond P.

doi:10.1073/pnas.1530168100

Cited by 114 publications

(86 citation statements)

References 41 publications

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“…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: 68%

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: 68%

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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“…Whereas decreased glutamate concentration due to GCPII inhibition could certainly contribute to cognitive sparing in EAE, it is hypothesized that NAAG is the crucial signaling messenger that ameliorated cognitive function in the present study. Inhibition of GCPII, which induces a measurable up-regulation in NAAG, has proved to be beneficial in treating various preclinical models of neurological disease (18,35,36). Activation of mGluR3 on presynaptic neurons by NAAG decreases glutamate release (37)(38)(39), potentially promoting the survival of neurons crucial to cognitive function.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Rahn

Watkins

Alt³

et al. 2012

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

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Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.G lutamate carboxypeptidase II (GCPII), previously called Nacetylated-α-linked acidic dipeptidase (NAALADase), is a membrane-bound enzyme expressed on the surface of astrocytes that catalyzes the cleavage of N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate ( Fig. 1) (1, 2). NAAG, the most abundant neuropeptide in the mammalian brain, is a selective agonist for metabotropic glutamate receptor 3 (mGluR3) (1, 2). mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS. Activation of mGluR3s by NAAG reduces cAMP and cGMP levels, inhibits glutamate release, and stimulates a release of transforming growth factor beta (1, 2). A recent study reported impaired performance on spatial reference and working memory tasks in mGluR2/3 knockout mice (3), suggesting a role for group II mGluRs in cognitive function.Cognitive impairment is a frequent comorbidity of many neurological diseases, including multiple sclerosis (MS). MS affects over 2 million individuals worldwide, and ∼40-65% of all MS patients experience cognitive impairment (4). The most commonly and severely affected facets of cognition in MS patients are anterograde episodic memory, working memory, and processing speed (5-7), and these impairments strongly contribute to the high frequency of unemployment in MS patient populations (8). Global brain atrophy, candidate genetic risk factors, accelerated inflammatory processes (7), and dysregulated signaling pathways (9) have been implicated as contributing factors, but an incomplete understanding of the molecular mechanisms behind cognitive impairment in MS has prevented the development and Food and Drug Administration (FDA) approval of drug therapies.The most widely used animal model of MS, experimental autoimmune encephalomyelitis (EAE), is a valuable tool for developing treatments for MS. Three FDA-approved disease-modifying agents were deve...

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“…248 Nevertheless, with most of the effects of riluzole being indirect, one can argue that more specifically targeted drugs or a combination of these could exhibit a greater therapeutic effect. When we review the previous drug-based therapeutic strategies targeting glutamate-mediated excitotoxicity in mice (AMPA antagonist, 183 EAAT2 upregulation, 118,119 and caboxypeptidase II inhibition), 249 none was found to consistently modify disease onset and all only modestly extended animal life span (6%-15%). In human clinical trials, treatment with the AMPA/KA antagonist topiramate worsened the patient's condition as it accelerated loss of muscle strength and elicited a series of adverse effects.…”

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

Cited by 114 publications

References 41 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

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

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

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