Deletion of the inflammatory S100-A9/MRP14 protein does not influence survival in hSOD1G93A ALS mice

Ribon, M; Leone, Céline; Chiot, Aude; Berriat, Félix; Rampanana, Martine; Cottin, Julie; Bohl, Delphine; Millecamps, Stéphanie; Lobsiger, Christian S.; Heneka, Michael T.; Boillée, Séverine

doi:10.1016/j.neurobiolaging.2021.01.015

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…Transthyretin (TTR) was shown to be dysregulated in ALS compared to control spinal cord samples [60] and Beta 2-microglobulin (B2M) has shown differential RNA expression in the peripheral white blood cells of ALS patients compared to control [61], making them potential biomarkers. S100-A9 mRNA levels were increased at end-stage ALS but deleting it in a mouse model had no impact on motor neuron survival and slightly accelerated symptoms [62]. In one study, S100B was found to be upregulated in ALS spinal cord samples [63], but in another, levels decreased with disease progression [64].…”

Section: Key Proteinsmentioning

confidence: 99%

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Venkatraman¹,

Filiano²,

Li³

et al. 2022

Cureus

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Introduction: Cerebrospinal fluid (CSF) has been implicated in amyotrophic lateral sclerosis (ALS) due to its ability to spread inflammatory proteins throughout the nervous system. We hypothesized that filtration of the CSF could remove pathogenic proteins and prevent them from altering motor phenotypes in a mouse model.Methods: We filtered the CSF from 11 ALS patients via 100 kilodaltons (kD) molecular weight cut-off filters. We used mass spectrometry-based discovery proteomics workflows to compare protein abundances before and after filtration. To test the effects of CSF filtration on motor function, we injected groups of mice with saline, filtered ALS-CSF, or unfiltered ALS-CSF (n=12 per group) and assessed motor function via pole descent and open field tests.Results: We identified proteins implicated in ALS pathogenesis and showed that these were removed in significant amounts in our workflow. Key filtered proteins included complement proteins, chitinases, serine protease inhibitors, and neuro-inflammatory proteins such as amyloid precursor protein, chromogranin A, and glial fibrillary acidic protein. Compared to the filtered ALS-CSF mice, unfiltered ALS-CSF mice took longer to descend a pole (10 days post-injection, 11.14 seconds vs 14.25 seconds, p = 0.02) and explored less on an open field (one day post-injection, 21.81 m vs 16.83 m, p = 0.0004).Conclusions: We demonstrated the ability to filter proteins from the CSF of ALS patients and identified potentially pathologic proteins that were reduced in quantity. Additionally, we demonstrated the ability of unfiltered ALS-CSF to induce motor deficits in mice on the pole descent and open field tests and showed that filtration could prevent this deficit. Given the lack of effective treatments for ALS, this could be a novel solution for patients suffering from this deadly and irreversible condition.

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Section: Key Proteinsmentioning

confidence: 99%

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Venkatraman¹,

Filiano²,

Li³

et al. 2022

Cureus

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show abstract

“…(iii) phase III, representing the time window between the mean day in which mice lost 5% of body weight and the mean day in which they lost 10% of body weight (Ribon et al, 2021).…”

Section: Body Weight Lossmentioning

confidence: 99%

Montelukast improves disease outcome in SOD1^G93A female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity

Raffaele,

Nguyen,

Milanese

et al. 2024

British J Pharmacology

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Background and PurposeAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro‐regenerative local milieu and re‐establish proper oligodendrocyte functions may be beneficial.Experimental ApproachHere, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein‐coupled receptor 17 (GPR17) and of cysteinyl‐leukotriene receptor 1 (CysLT1R) receptors on microglia and astrocytes, in the SOD1G93A ALS mouse model. We chronically treated SOD1G93A mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.Key ResultsOral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1G93A mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1G93A mice, suggesting enhanced pro‐regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex‐based difference in the protective activity of MTK.Conclusions and ImplicationsOur results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti‐asthmatic drug, may be a promising sex‐specific strategy for personalized ALS treatment.

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Innate immune activation in neurodegenerative diseases

Castro-Gomez,

Heneka

2024

Immunity

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Deletion of the inflammatory S100-A9/MRP14 protein does not influence survival in hSOD1G93A ALS mice

Cited by 4 publications

References 23 publications

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Montelukast improves disease outcome in SOD1^G93A female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity

Innate immune activation in neurodegenerative diseases

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Deletion of the inflammatory S100-A9/MRP14 protein does not influence survival in hSOD1G93A ALS mice

Cited by 4 publications

References 23 publications

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Montelukast improves disease outcome in SOD1G93A female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity

Innate immune activation in neurodegenerative diseases

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Product

Resources

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Montelukast improves disease outcome in SOD1^G93A female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity