A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS

Hatzipetros, Theo; Kidd, Joshua D.; Moreno, Andy J.; Thompson, Kenneth; Gill, Alan; Vieira, Fernando

doi:10.3791/53257

Cited by 76 publications

(78 citation statements)

References 15 publications

(12 reference statements)

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“…We then explored the impact of astrocytic NF-jB activation on disease progression in SOD1/IKK mice. Although survival of SOD1/ IKK and SOD1 littermates was comparable (Mantel-Cox, P = 0.5763; Fig 4A), SOD1/IKK mice reached motor impairment (Hatzipetros et al, 2015) stages 1, 2, and 3 significantly later than their SOD1 counterparts (SOD1 stayed in stage 1 from day 77-91 versus 84-122 of SOD1/IKK; P < 0.05; SOD1 stayed in stage 2 from day 84-105 versus 109-126; P < 0.05; stage 3 from day 105-119 versus 125-136; P < 0.05; Fig 4B; IKK mice displayed no motor phenotypes). However, later in disease, stages 4 and 5 were reached at comparable time points (day 133-140; Fig 4B).…”

Section: E and F)mentioning

confidence: 92%

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NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

et al. 2018

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Astrocytes are involved in non‐cell‐autonomous pathogenic cascades in amyotrophic lateral sclerosis (ALS); however, their role is still debated. We show that astrocytic NF‐κB activation drives microglial proliferation and leukocyte infiltration in the SOD1 (G93A) ALS model. This response prolongs the presymptomatic phase, delaying muscle denervation and decreasing disease burden, but turns detrimental in the symptomatic phase, accelerating disease progression. The transition corresponds to a shift in the microglial phenotype showing two effects that can be dissociated by temporally controlling NF‐κB activation. While NF‐κB activation in astrocytes induced a Wnt‐dependent microglial proliferation in the presymptomatic phase with neuroprotective effects on motoneurons, in later stage, astrocyte NF‐κB‐dependent microglial activation caused an accelerated disease progression. Notably, suppression of the early microglial response by CB2R agonists had acute detrimental effects. These data identify astrocytes as important regulators of microglia expansion and immune response. Therefore, stage‐dependent microglia modulation may be an effective therapeutic strategy in ALS.

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Section: E and F)mentioning

confidence: 92%

“…Body weight for all four genotypes was obtained every 3 days. Clinical score was evaluated according to Hatzipetros et al (2015). End stage was determined as the time point where animals could no longer right themselves from the back within 15-30 s (Ludolph et al, 2007).…”

Section: Body Weight and Clinical Assessmentmentioning

confidence: 99%

NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

et al. 2018

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“…Neurological score is a phenotypic scoring system that includes five scores ranging from 0, for symptoms free animals, to 4 for end stage animal where mouse cannot right itself within 30 seconds after being placed on either side. Therefore, for asymptomatic ALS stage, mice below age of 70 days with neurological score of 0 were used, whereas mice over 120 days old with neurological scores of 2–3 have been used as symptomatic ALS mice (Hatzipetros et al, 2015). Our SOD1-G93A mouse colony have 50% survival rate at 157.1 ± 9.3 days.…”

Section: Methodsmentioning

confidence: 99%

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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“…ISRIB concentrations were determined in venous blood two weeks after start of the injections and in post-mortem blood and brain as previously described (15) Motor skills (neuroscores, Balance Beam) were assessed at indicated time points as previously described (10,73). Mice were subjected to a catwalk set-up for a quantitative gait analysis, using CatWalk XT 10.6 (Noldus Information Technology) prior to being euthanized.…”

Section: Isrib Trialmentioning

confidence: 99%

Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

Abbink

Wisse

Jaku

et al. 2018

Preprint

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Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation under stress conditions. Mice with bi-allelic missense mutations in eIF2B recapitulate human VWM. VWM pathomechanisms are unclear. Using polysomal profiling to screen for mRNAs with altered translation we observed most prominent changes in expression of integrated stress response (ISR) mRNAs in brains of mutant compared to wild-type mice; expression levels correlated with disease severity. We substantiated these findings in VWM patients' brains.ISRIB, an ISR inhibitor, normalized expression of mRNA markers, ameliorated white matter pathology and improved motor skills in VWM mice, thus showing that the ISR is central in VWM pathomechanisms and a viable target for therapy.

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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS

Cited by 76 publications

References 15 publications

NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

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

Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

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