Lack of TNF‐alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression

Tortarolo, Massimo; Vallarola, Antonio; Lidonnici, D.; Battaglia, Elisa; Gensano, Francesco; Spaltro, Gabriella; Fiordaliso, Fabio; Corbelli, Alessandro; Garetto, Stefano; Martini, Elisa; Pasetto, Laura; Kallikourdis, Marinos; Bonetto, Valentina; Bendotti, Caterina

doi:10.1111/jnc.13154

Cited by 33 publications

(53 citation statements)

References 48 publications

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“…We previously reported that SOD1 G93A expression in both astrocytes and motor neurons determines selective motor neuron death under co-culture conditions 23 . In agreement with previous findings, there were significantly fewer large motor neurons in the AST G93A NEU G93A compared to the AST NTG NEU NTG co-cultures grown for six days in vitro (DIV) after neuron plating, while the number of total spinal neurons remained unchanged (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The mice were bred and maintained in a specific-pathogen-free environment. We used NTG and SOD1 G93A mice originally purchased from Jackson Laboratories (B6SJL-Tg-SOD1-G93A-1Gur) and maintained on a C57BL/6JOlaHsd (Harlan) genetic background at the IRFMN 23 . The genotype of the embryos was determined by PCR analysis of DNA extracted from tissue biopsies.…”

Section: Methodsmentioning

confidence: 99%

“…Astrocytes, in particular, are likely to take part in processes leading to motor neuron injury and contribute to disease progression 19–22 . We have previously shown that motor neurons isolated from mutant SOD1 G93A embryos do not die when spinal neurons are cultured on their own, but become selectively vulnerable if co-cultured with transgenic SOD1 G93A astrocytes 23 .…”

Section: Introductionmentioning

confidence: 99%

“…We used co-cultures of astrocytes and spinal neurons obtained from SOD1 G93A embryos and their non-transgenic counterparts, a model that we have previously characterized to exhibit spontaneous and selective loss of motor neurons 23 . We measured the change in extracellular metabolite concentrations compared to fresh media of co-cultures of non-transgenic and transgenic SOD1 G93A astrocytes and spinal neurons, providing information on net uptake or net release of metabolites over the periods of incubation.…”

Section: Introductionmentioning

confidence: 99%

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Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures

Valbuena

Tortarolo

Bendotti

et al. 2017

Sci Rep

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Non-cell autonomous processes involving astrocytes have been shown to contribute to motor neuron degeneration in amyotrophic lateral sclerosis. Mutant superoxide dismutase 1 (SOD1 G93A ) expression in astrocytes is selectively toxic to motor neurons in co-culture, even when mutant protein is expressed only in astrocytes and not in neurons. To examine metabolic changes in astrocyte-spinal neuron cocultures, we carried out metabolomic analysis by 1 H NMR spectroscopy of media from astrocyte-spinal neuron co-cultures and astrocyte-only cultures. We observed increased glucose uptake with SOD1 G93A expression in all co-cultures, but while co-cultures with only SOD1 G93A neurons had lower extracellular lactate, those with only SOD1 G93A astrocytes exhibited the reverse. Reduced branched-chain amino acid uptake and increased accumulation of 3-methyl-2-oxovalerate were observed in co-culture with only SOD1 G93A neurons while glutamate was reduced in all co-cultures expressing SOD1 G93A . The shifts in these coupled processes suggest a potential block in glutamate processing that may impact motor neuron survival. We also observed metabolic alterations which may relate to oxidative stress responses. Overall, the different metabolite changes observed with the two SOD1 G93A cell types highlight the role of the astrocyte-motor neuron interaction in the resulting metabolic phenotype, requiring further examination of altered met abolic pathways and their impact on motor neuron survival.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons, leading to progressive neuromuscular impairment and death, usually within 2-3 years after diagnosis. Around 10% of ALS cases are due to inherited genetic mutations, with those in the Cu-Zn superoxide dismutase gene (SOD1) first to be associated with the disease. Rodents expressing SOD1 mutations invariably develop a motor syndrome with pathological and symptomatic features of the human disease, therefore representing the best experimental models of ALS available. To date, the process by which mutant SOD1 leads to toxicity has not yet been fully resolved, although oxidative stress, excitotoxicity, dysregulation of energy metabolism, and mitochondrial dysfunction have been extensively studied as potential pathogenic mechanisms, based on studies of patient tissues and experimental models of the disease 1-3 . A complex multifactorial pathogenesis would be compatible with a key toxic role for global derangements in metabolism.Metabolomic and proteomic analysis of biofluids from ALS patients have revealed altered profiles and are being applied in search of biomarkers for diagnosis [4][5][6] . However, there is still limited information available on the effect of mutant SOD1 expression on metabolism in the different cell types of the nervous system. Our group has previously shown that while expression of wild type human SOD1 in the NSC-34 cell line reinforced metabolic responses to stress, this process was dysregulated with expression of mutan...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures

Valbuena

Tortarolo

Bendotti

et al. 2017

Sci Rep

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“…However, genetic ablation of TNFα had no effect on motor neuron degeneration in ALS-linked mutant hSOD1 mouse models [133]. In addition, deletion of TNFR2 in hSOD1 G93A mice partially protects motor neurons but does not improve motor deficits or survival [134]. Moreover, TNFR1 deletion accelerates motor neuron degeneration and disease progression in the same model, an effect attributed to the disruption of the astrocytic TNFR1-GDNF axis [135].…”

Section: Pathways Involved In Astrocyte-mediated Motor Neuron Toximentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis

Qosa

Lichter

Sarlo

et al. 2016

Glia

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The efficacy of drugs targeting the CNS is influenced by their limited brain access, which can lead to complete pharmacoresistance. We recently reported a tissue-specific and selective upregulation of the multidrug efflux transporter ABCB1 or P-glycoprotein (P-gp) in the spinal cord of both patients and the mutant SOD1-G93A mouse model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that prevalently kills motor neurons. Here, we have extended the analysis of P-gp expression in the SOD1-G93A ALS mouse model and found that P-gp upregulation was restricted to endothelial cells of the capillaries, while P-gp expression was not detected in other cells of the spinal cord parenchyma such as astrocytes, oligodendrocytes, and neurons. Using both in vitro human and mouse models of the blood-brain barrier (BBB), we found that mutant SOD1 astrocytes were driving P-gp upregulation in endothelial cells. In addition, we observed a significant increase in reactive oxygen species production, Nrf2 and NFκB activation in endothelial cells exposed to mutant SOD1 astrocytes in both human and murine BBB models. Most interestingly, astrocytes expressing FUS-H517Q, a different familial ALS-linked mutated gene, also drove NFκB-dependent upregulation of P-gp. However, the pathway was not dependent on oxidative stress but rather involved TNFα release. Overall, our findings indicate that nuclear translocation of NFκB is a converging mechanism used by endothelial cells of the BBB to upregulate P-gp expression in mutant SOD1-linked ALS and possibly other forms of familial ALS.

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Lack of TNF‐alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression

Cited by 33 publications

References 48 publications

Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures

Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis

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