A beneficial role for elevated extracellular glutamate in Amyotrophic Lateral Sclerosis and cerebral ischemia

Schiel, Kathryn A.

doi:10.1002/bies.202100127

Cited by 5 publications

(3 citation statements)

References 134 publications

(192 reference statements)

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“…53 In this regard, several lines of evidence also suggest that excessive activation of the glutamate receptors results in excitotoxicity. [53][54][55] With the GRIK1 gene being hypermethylated (or presumably transcriptionally suppressed) in ALS samples, our findings implicate the activation of a compensatory mechanism responsible for restoring the overly active glutamate signaling back to normal levels in ALS. Further research is needed to confirm this hypothesis and to understand the potential role of GRIK1 in ALS biology.…”

Section: Discussionmentioning

confidence: 69%

DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells

et al. 2023

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ALS is a fatal motor neuron disease that displays a broad variety of phenotypes ranging from early fatal courses to slowly progressing and rather benign courses. Such divergence can also be seen in genetic ALS cases with varying phenotypes bearing specific mutations, suggesting epigenetic mechanisms like DNA methylation act as disease modifiers. However, the epigenotype dictated by, in addition to other mechanisms, DNA methylation is also strongly influenced by the individual’s genotype. Hence, we performed a DNA methylation study using EPIC arrays on 7 monozygotic (MZ) twin pairs discordant for ALS in whole blood, which serves as an ideal model for eliminating the effects of the genetic-epigenetic interplay to a large extent. We found one CpG site showing intra-pair hypermethylation in the affected co-twins, which maps to the Glutamate Ionotropic Receptor Kainate Type Subunit 1 gene ( GRIK1). Additionally, we found 4 DMPs which were subsequently confirmed using 2 different statistical approaches. Differentially methylated regions or blocks could not be detected within the scope of this work. In conclusion, we revealed that despite a low sample size, monozygotic twin studies discordant for the disease can bring new insights into epigenetic processes in ALS, pointing to new target loci for further investigations.

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Section: Discussionmentioning

confidence: 69%

DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells

et al. 2023

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“…However, proving this hypothesis is currently challenging due to the limited data on the CSF volume in ALS patients. Nonetheless, most of this theory is supported by evidence of spinal cord and cortical compression (for a comprehensive overview see [55]).…”

Section: Glutamate-mediated Excitotoxicitymentioning

confidence: 99%

Pathophysiology of ion channels in amyotrophic lateral sclerosis

Stringer,

Weiss

2023

Mol Brain

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Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.

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“…There is mounting evidence that Glu excitotoxicity plays a role in slow-evolving neurodegeneration 13 , 14 . Glu excitotoxicity is thought to be the final common pathway of neuronal injury for some degenerative neural disorders, such as AD 15 , AIDS dementia 16 , Amyotrophic Lateral Sclerosis 17 , and Parkinson's Disease 18 . Furthermore, earlier studies provided evidence that Glu-induced neurotoxicity is one of the most critical factors leading to the loss of neurons in AD 19 .…”

Section: Introductionmentioning

confidence: 99%

Moschus ameliorates glutamate-induced cellular damage by regulating autophagy and apoptosis pathway

Xie,

Song,

Qin

et al. 2023

Sci Rep

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Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or other dementias. Chinese herbal medicine as a potential drug for treating AD has gained growing interest from many researchers. Moschus, a rare and valuable traditional Chinese animal medicine, was originally documented in Shennong Ben Cao Jing and recognized for its properties of reviving consciousness/resuscitation. Additionally, Moschus has the efficacy of “regulation of menstruation with blood activation, relief of swelling and pain” and is used for treating unconsciousness, stroke, coma, and cerebrovascular diseases. However, it is uncertain whether Moschus has any protective effect on AD patients. We explored whether Moschus could protect glutamate (Glu)-induced PC12 cells from cellular injury and preliminarily explored their related action mechanisms. The chemical compounds of Moschus were analyzed and identified by GC–MS. The Glu-induced differentiated PC12 cell model was thought to be the common AD cellular model. The study aims to preliminarily investigate the intervention effect of Moschus on Glu-induced PC12 cell damage as well as their related action mechanisms. Cell viability, lactate dehydrogenase (LDH), mitochondrial reactive oxygen species, mitochondrial membrane potential (MMP), cell apoptosis, autophagic vacuoles, autolysosomes or autophagosomes, proteins related to apoptosis, and the proteins related to autophagy were examined and analyzed. Seventeen active compounds of the Moschus sample were identified based on GC–MS analysis. In comparison to the control group, Glu stimulation increased cell viability loss, LDH release, mitochondrial damage, loss of MMP, apoptosis rate, and the number of cells containing autophagic vacuoles, and autolysosomes or autophagosomes, while these results were decreased after the pretreatment with Moschus and 3-methyladenine (3-MA). Furthermore, Glu stimulation significantly increased cleaved caspase-3, Beclin1, and LC3II protein expression, and reduced B-cell lymphoma 2/BAX ratio and p62 protein expression, but these results were reversed after pretreatment of Moschus and 3-MA. Moschus has protective activity in Glu-induced PC12 cell injury, and the potential mechanism might involve the regulation of autophagy and apoptosis. Our study may promote research on Moschus in the field of neurodegenerative diseases, and Moschus may be considered as a potential therapeutic agent for AD.

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A beneficial role for elevated extracellular glutamate in Amyotrophic Lateral Sclerosis and cerebral ischemia

Cited by 5 publications

References 134 publications

DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells

DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells

Pathophysiology of ion channels in amyotrophic lateral sclerosis

Moschus ameliorates glutamate-induced cellular damage by regulating autophagy and apoptosis pathway

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