The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

Blasco, Hélène; Mavel, Sylvie; Corcia, Philippe; Gordon, Paul H.

doi:10.2174/0929867321666140916120118

Cited by 141 publications

(95 citation statements)

References 321 publications

(388 reference statements)

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“…Pathway analysis showed in ALS patients major down-regulations in genes related to glutamate metabolism, such as CCBL2 , also called KAT3 (Kynurenine aminotransferase), supporting the role of glutamate-induced excitotoxicity in ALS pathogenesis, coherently with previous reports35. KAT3 catalyzes the synthesis of kynurenic acid (KYNA), a known endogenous antagonist of the NMDA (n-methil-D-aspartate) glutamate receptors.…”

Section: Discussionsupporting

confidence: 83%

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Riva

Clarelli

Domi

et al. 2016

Sci Rep

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The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies.

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Section: Discussionsupporting

confidence: 83%

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Riva

Clarelli

Domi

et al. 2016

Sci Rep

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“…It is unclear whether there are any compensatory mechanisms such as glutamate transporters that are at work in these mice. Previous studies employed deregulation or loss of function of glutamate transporters EAAT1 and EAAT2 located on astrocytes, which led to neural inflammation and cell death similar to our Tg mice (Blasco et al, 2014; Masliah et al, 1996). …”

Section: Discussionmentioning

confidence: 84%

Glutaminase C overexpression in the brain induces learning deficits, synaptic dysfunctions, and neuroinflammation in mice

Wang

Zhao

et al. 2017

Brain, Behavior, and Immunity

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Glutaminolysis, a metabolic process that converts glutamine to glutamate, is particularly important for the central nervous system since glutamate is the major transmitter of excitatory synapses. Glutaminase is the mitochondrial enzyme that catalyzes the first step of glutaminolysis. Two genes encode at least four isoforms of glutaminase in humans. GLS1 gene encodes isoforms kidney-type glutaminase and glutaminase C (GAC) through alternative splicing, whereas GLS2 gene encodes liver-type glutaminase isoforms. KGA and GAC have been associated with several neurological diseases. However, it remains unclear whether changes in their expressions can directly cause brain abnormalities. Using a transgenic approach, we generated mice that overexpressed GAC in the brain. The resulting transgenic mice had severe impairments in spatial and fear learning compared with littermate controls. The learning deficits were consistent with diminished hippocampal long-term potentiation in the hippocampal slices of the GAC transgenic mice. Furthermore, we found increases in astrocyte and microglia markers, inflammatory factors, and a decrease in synapse marker synaptophysin, suggesting neuroinflammation and synaptic changes in the GAC transgenic mouse brains. In conclusion, these findings provide the first evidence that GAC overexpression in the brain has deleterious effects on learning and synaptic integrity in vivo.

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“…While there is evidence of numerous pathologic mechanisms associated with ALS, excitoxicity continues to be one of the accepted mediators of disease progression and MN death and has been studied extensively [74][75][76]. Excitoxicity is a result of overstimulation of glutamate receptors, thereby increasing intracellular calcium levels leading to increased cell death.…”

Section: Metabolic Biomarkersmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

Cited by 141 publications

References 321 publications

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Glutaminase C overexpression in the brain induces learning deficits, synaptic dysfunctions, and neuroinflammation in mice

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

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