NADPH oxidase (NOX2) activity is a modifier of survival in ALS

Marrali, Giuseppe; Casale, Federico; Salamone, Paolina; Fuda, Giuseppe; Caorsi, Cristiana; Amoroso, Antonio; Brunetti, Maura; Restagno, Gabriella; Barberis, Marco; Bertuzzo, Davide; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; Chiò, Adriano

doi:10.1007/s00415-014-7470-0

Cited by 35 publications

(22 citation statements)

References 28 publications

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“…These astrocytes also expressed cleaved caspase-3 and NOX2. The NADPH-oxidase NOX2 generates ROS, which are known to induce oxidative stress and one of the modifiers of ALS disease [43, 44]. Therefore, these abnormally activated astrocytes are likely to be harmful to spinal motor neurons by generating ROS.…”

Section: Discussionmentioning

confidence: 99%

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

et al. 2018

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There is compelling evidence that glial-immune interactions contribute to the progression of neurodegenerative diseases. The adaptive immune response has been implicated in disease processes of amyotrophic lateral sclerosis (ALS), but it remains unknown if innate immune signaling also contributes to ALS progression. Here we report that deficiency of the innate immune adaptor TIR domain-containing adaptor inducing interferon-β (TRIF), which is essential for certain Toll-like receptor (TLR) signaling cascades, significantly shortens survival time and accelerates disease progression of ALS mice. While myeloid differentiation factor 88 (MyD88) is also a crucial adaptor for most TLR signaling pathways, MyD88 deficiency had only a marginal impact on disease course. Moreover, TRIF deficiency reduced the number of natural killer (NK), NK-T-lymphocytes, and CD8-T cells infiltrating into the spinal cord of ALS mice, but experimental modulation of these populations did not substantially influence survival time. Instead, we found that aberrantly activated astrocytes expressing Mac2, p62, and apoptotic markers were accumulated in the lesions of TRIF-deficient ALS mice, and that the number of aberrantly activated astrocytes was negatively correlated with survival time. These findings suggest that TRIF pathway plays an important role in protecting a microenvironment surrounding motor neurons by eliminating aberrantly activated astrocytes.

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Section: Discussionmentioning

confidence: 99%

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

et al. 2018

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“…In regard to ALS, the focus is more clearly on the therapeutic benefits of inactivation of NOX. For example, NOX2 activity in 83 ALS patients was assessed by measuring neutrophil oxidative burst in fresh blood samples by flow cytometry (Marrali et al ., ). Although the activity of the enzyme was independent of gender and disease duration, a lower NOX2 level correlated with a longer survival time from disease onset.…”

Section: Nox‐based Therapies In Neurodegenerative Diseasementioning

confidence: 97%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

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“…Based on the potential role of NOX enzymes in ALS pathology, it is reasonable to investigate whether targeting of NOX can be therapeutic. Studies investigating NOX’s role in human ALS patients found that patients that had lower NOX2 activity in their peripheral blood cells showed significant increases in survival [275]. Additionally, ALS mice deficient in NOX2 showed decreased oxidative stress in spinal cords and a modest increase in lifespan (Table 2) [262].…”

Section: Introductionmentioning

confidence: 99%

NADPH oxidase in brain injury and neurodegenerative disorders

Merry

Wang

Zhang

et al. 2017

Mol Neurodegeneration

342

309

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Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.

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NADPH oxidase (NOX2) activity is a modifier of survival in ALS

Cited by 35 publications

References 28 publications

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

Redox‐based therapeutics in neurodegenerative disease

NADPH oxidase in brain injury and neurodegenerative disorders

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