N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

Morland, Cecilie; Nordengen, Kaja

doi:10.3390/ijms23031268

Cited by 43 publications

(40 citation statements)

References 137 publications

(164 reference statements)

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“…Furthermore, NAALAD2 has molecular specificity for TD because it works on two important, TD-linked neurotransmitters: NAAG and glutamate. NAAG is one of the only CSF markers for which we found genetic sharing with TD and it is thought to function as a neurotransmitter in both the CNS and peripheral nervous system, with its lowest expression being in the pituitary [ 234 ], a finding that is in line with NAALAD2 expression being the highest in this brain region (see above). In a magnetic resonance spectroscopy (MRS) study, patients with TD also had reduced levels of NAA in the left putamen and bilateral frontal cortex [ 191 ].…”

Section: Discussionsupporting

confidence: 63%

Molecular Landscape of Tourette’s Disorder

Widomska

Witte

Buitelaar

et al. 2023

IJMS

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Tourette’s disorder (TD) is a highly heritable childhood-onset neurodevelopmental disorder and is caused by a complex interplay of multiple genetic and environmental factors. Yet, the molecular mechanisms underlying the disorder remain largely elusive. In this study, we used the available omics data to compile a list of TD candidate genes, and we subsequently conducted tissue/cell type specificity and functional enrichment analyses of this list. Using genomic data, we also investigated genetic sharing between TD and blood and cerebrospinal fluid (CSF) metabolite levels. Lastly, we built a molecular landscape of TD through integrating the results from these analyses with an extensive literature search to identify the interactions between the TD candidate genes/proteins and metabolites. We found evidence for an enriched expression of the TD candidate genes in four brain regions and the pituitary. The functional enrichment analyses implicated two pathways (‘cAMP-mediated signaling’ and ‘Endocannabinoid Neuronal Synapse Pathway’) and multiple biological functions related to brain development and synaptic transmission in TD etiology. Furthermore, we found genetic sharing between TD and the blood and CSF levels of 39 metabolites. The landscape of TD not only provides insights into the (altered) molecular processes that underlie the disease but, through the identification of potential drug targets (such as FLT3, NAALAD2, CX3CL1-CX3CR1, OPRM1, and HRH2), it also yields clues for developing novel TD treatments.

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Section: Discussionsupporting

confidence: 63%

Molecular Landscape of Tourette’s Disorder

Widomska

Witte

Buitelaar

et al. 2023

IJMS

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“…This process can be reduced with an effective P/Q-type VGCCs modulator (Schurr, 2004;Nimmrich and Gross, 2012). Based on some previous studies on excitotoxicity models, hyperstimulation of glutamate receptors is a result of the administration of NMDA in the rat hippocampus (Jarrard, 2002;Gilmour et al, 2012;Farzamfard et al, 2022;Morland and Nordengen, 2022).…”

Section: Discussionmentioning

confidence: 99%

Ameliorative effects of omega-lycotoxin-Gsp2671e purified from the spider venom of Lycosa praegrandis on memory deficits of glutamate-induced excitotoxicity rat model

et al. 2022

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Memory impairment is one of the main complications of Alzheimer’s disease (AD). This condition can be induced by hyper-stimulation of N-Methyl-D-aspartate receptors (NMDARs) of glutamate in the hippocampus, which ends up to pyramidal neurons determination. The release of neurotransmitters relies on voltage-gated calcium channels (VGCCs) such as P/Q-types. Omega-lycotoxin-Gsp2671e (OLG1e) is a P/Q-type VGCC modulator with high affinity and selectivity. This bio-active small protein was purified and identified from the Lycosa praegrandis venom. The effect of this state-dependent low molecular weight P/Q-type calcium modulator on rats was investigated via glutamate-induced excitotoxicity by N-Methyl-D-aspartate. Also, Electrophysiological amplitude of field excitatory postsynaptic potentials (fEPSPs) in the input–output and Long-term potentiation (LTP) curves were recorded in mossy fiber and the amount of synaptophysin (SYN), synaptosomal-associated protein, 25 kDa (SNAP-25), and synaptotagmin 1(SYT1) genes expression were measured using Real-time PCR technique for synaptic quantification. The outcomes of the current study suggest that OLG1e as a P/Q-type VGCC modulator has an ameliorative effect on excitotoxicity-induced memory defects and prevents the impairment of pyramidal neurons in the rat hippocampus.

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“…Post-synaptic neuronal GRM3 activation by NAAG results in inhibition of downstream signaling, resulting in reduced release of glutamate by post-synaptic neurons and thus may modify neuronal activity in conjunction with co-released glutamate. In epilepsy models, inhibition of the NAAG degradation enzyme (glutamate carboxypeptidase II) and GRM3 agonists module seizure frequency [ 56 ], and activation of GRM3 in traumatic brain injury models indicates a protective effect. With expression in astrocytes, it has been suggested that NAAG may also play a role in mediating inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia

Leitner

Kanshin²,

Askenazi

et al. 2022

PLoS ONE

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Background Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways. Methods and findings We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4–26; n = 10, Control, mean age 13.1, range 3–45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences. Conclusions Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects. Clinical trials registration ClinicalTrials.gov NCT02451696.

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N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

Cited by 43 publications

References 137 publications

Molecular Landscape of Tourette’s Disorder

Molecular Landscape of Tourette’s Disorder

Ameliorative effects of omega-lycotoxin-Gsp2671e purified from the spider venom of Lycosa praegrandis on memory deficits of glutamate-induced excitotoxicity rat model

Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia

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