Genetic Variability of Inflammation and Oxidative Stress Genes Affects Onset, Progression of the Disease and Survival of Patients with Amyotrophic Lateral Sclerosis

Ravnik‐Glavač, Metka; Goričar, Katja; Vogrinc, David; Koritnik, Blaž; Lavrenčič, Jakob Gašper; Glavač, Damjan; Dolžan, Vita

doi:10.3390/genes13050757

Cited by 11 publications

(10 citation statements)

References 81 publications

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“…In this work, we have shown that modulation of gzmA can regulate some pro-inflammatory cytokines and one oxidative stress enzyme, suggesting that several pathways involved in the pathogenesis of ALS could be targeted when modulating gzmA. Supporting our results, a previous study reported that genetic variability of both inflammation and oxidative stress genes can affect the onset and the course of the disease in patients with ALS [ 59 ]. However, modulation of the immune system is challenging, as we have demonstrated in this study that a complete suppression of gzmA did not show the best results, but a partial reduction of gzmA was sufficient to modulate the gzmA-dependent pro-inflammatory cytokine response.…”

Section: Discussionsupporting

confidence: 87%

Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan

Moreno-Martínez

Santiago

Torre

et al. 2022

IJMS

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Granzyme A (gzmA), a serine protease involved in the modulation of the inflammatory immune response, is found at an elevated level in the serum from ALS patients. However, the influence of gzmA on the progression of ALS remains unclear. The aim of our work was to assess whether the absence of gzmA in an ALS murine model could help slow down the progression of the disease. Homozygous and hemizygous gzmA-deficient mice expressing the hSOD1G93A transgene were generated, and survival of these mice was monitored. Subsequently, gene and protein expression of inflammatory and oxidative stress markers was measured in the spinal cord and quadriceps of these mice. We observed the longest lifespan in gzmA+/− mice. GzmA gene and protein expression was downregulated in the spinal cord and serum from gmzA+/− mice, confirming that the increased survival of hemizygous mice is correlated with lower levels of gzmA. In addition, mRNA and protein levels of glutathione reductase (GSR), involved in oxidative stress, were found downregulated in the spinal cord and quadriceps of gmzA+/− mice, together with lower IL-1β and IL-6 mRNA levels in hemyzigous mice. In summary, our findings indicate for the first time that reduced levels, but not the absence, of gzmA could slightly ameliorate the disease progression in this animal model.

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Section: Discussionsupporting

confidence: 87%

Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan

Moreno-Martínez

Santiago

Torre

et al. 2022

IJMS

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“… 273 These genes have been discussed in multiple reviews recently. 273 , 274 We will not discuss them in depth.…”

Section: Probable Inducers Of Inflammation In Neurodegenerationmentioning

confidence: 99%

Role of neuroinflammation in neurodegeneration development

Zhang

Xiao

Mao

et al. 2023

Sig Transduct Target Ther

205

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Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s disease, and so on, have suggested that inflammation is not only a result of neurodegeneration but also a crucial player in this process. Protein aggregates which are very common pathological phenomenon in neurodegeneration can induce neuroinflammation which further aggravates protein aggregation and neurodegeneration. Actually, inflammation even happens earlier than protein aggregation. Neuroinflammation induced by genetic variations in CNS cells or by peripheral immune cells may induce protein deposition in some susceptible population. Numerous signaling pathways and a range of CNS cells have been suggested to be involved in the pathogenesis of neurodegeneration, although they are still far from being completely understood. Due to the limited success of traditional treatment methods, blocking or enhancing inflammatory signaling pathways involved in neurodegeneration are considered to be promising strategies for the therapy of neurodegenerative diseases, and many of them have got exciting results in animal models or clinical trials. Some of them, although very few, have been approved by FDA for clinical usage. Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis. We also summarize the current strategies, both in animal models and in the clinic, for the treatment of neurodegenerative diseases.

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“…In this regard, recently new polymorphisms in the gene encoding IL-1β and in genes involved in oxidative stress ( e.g. , SOD2) have been identified as modifiers of ALS progression ( 153 ). IL-1β is one of the main biomarkers of inflammation in ALS ( 151 , 152 ).…”

Section: Il-1 Family Molecules In Other Main Neurodegenerative Diseasesmentioning

confidence: 99%

Cause or consequence? The role of IL-1 family cytokines and receptors in neuroinflammatory and neurodegenerative diseases

et al. 2023

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Cytokines and receptors of the IL-1 family are key mediators in innate immune and inflammatory reactions in physiological defensive conditions, but are also significantly involved in immune-mediated inflammatory diseases. Here, we will address the role of cytokines of the IL-1 superfamily and their receptors in neuroinflammatory and neurodegenerative diseases, in particular Multiple Sclerosis and Alzheimer’s disease. Notably, several members of the IL-1 family are present in the brain as tissue-specific splice variants. Attention will be devoted to understanding whether these molecules are involved in the disease onset or are effectors of the downstream degenerative events. We will focus on the balance between the inflammatory cytokines IL-1β and IL-18 and inhibitory cytokines and receptors, in view of future therapeutic approaches.

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Genetic Variability of Inflammation and Oxidative Stress Genes Affects Onset, Progression of the Disease and Survival of Patients with Amyotrophic Lateral Sclerosis

Cited by 11 publications

References 81 publications

Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan

Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan

Role of neuroinflammation in neurodegeneration development

Cause or consequence? The role of IL-1 family cytokines and receptors in neuroinflammatory and neurodegenerative diseases

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