Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique

Weiduschat, Nora; Mao, Xiangling; Hupf, Jonathan; Armstrong, N.; Kang, Guoguo; Lange, Dale J.; Mitsumoto, Hiroshi; Shungu, Dikoma C.

doi:10.1016/j.neulet.2014.04.020

Cited by 99 publications

(91 citation statements)

References 31 publications

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“…Elevated levels of ROS accentuate the disease pathology by causing oxidative stress, as well as reducing the glutathione (GSH) levels [56, 57]. Similarly, apart from the free radical-mediated damage, NO is capable of inflicting neurodegeneration through apoptosis, which concurs with our previous report of the occurrence of both necrosis and apoptosis, i.e., “necroptosis” induced neuronal death in the disease pathogenesis [21, 25, 26].…”

Section: Discussionsupporting

confidence: 84%

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Mishra

Dhull

Nalini

et al. 2016

J Neuroinflammation

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BackgroundNon-cell autonomous toxicity is one of the potential mechanisms implicated in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). However, the exact role of glial cells in ALS pathology is yet to be fully understood. In a cellular model recapitulating the pathology of sporadic ALS, we have studied the inflammatory response of astroglia following exposure to the cerebrospinal fluid from ALS patients (ALS-CSF).MethodsVarious inflammatory markers including pro-inflammatory and anti-inflammatory cytokines, COX-2, PGE-2, trophic factors, glutamate, nitric oxide (NO), and reactive oxygen species (ROS) were analyzed in the rat astroglial cultures exposed to ALS-CSF and compared with the disease control or normal controls. We used immunofluorescence, ELISA, and immunoblotting techniques to investigate the protein expression and real-time PCR to study the messenger RNA (mRNA) expression. Glutamate, NO, and ROS were estimated using appropriate biochemical assays. Further, the effect of conditioned medium from the astroglial cultures exposed to ALS-CSF on NSC-34 motor neuronal cell line was detected using the MTT assay. Statistical analysis was carried out using one-way ANOVA followed by Tukey’s post hoc test, or Student’s t test, as applicable.ResultsHere, we report that the ALS-CSF enhanced the production and release of inflammatory cytokines IL-6 and TNF-α, as well as COX-2 and PGE-2. Concomitantly, anti-inflammatory cytokine IL-10 and the beneficial trophic factors, namely VEGF and GDNF, were down-regulated. We also found impaired regulation of glutamate, NO, and ROS in the astroglial cultures treated with ALS-CSF. The conditioned medium from the ALS-CSF exposed astroglial cultures induced degeneration in NSC-34 cells.ConclusionsOur study demonstrates that the astroglial cells contribute to the neuroinflammation-mediated neurodegeneration in the in vitro model of sporadic ALS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0698-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 84%

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Mishra

Dhull

Nalini

et al. 2016

J Neuroinflammation

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“…For instance, Shungu and colleagues (37) found that depressed patients had significantly lower levels of occipital glutathione than healthy volunteers. Reductions in glutathione have also been observed in amyotrophic lateral sclerosis (38) and chronic fatigue syndrome (37), suggesting that 1 H-MRS glutathione levels may be an index of oxidative stress, which commonly occurs in psychiatric and neurological conditions. We also noted a decrease in glutathione with age, which is particularly interesting because ageing is associated with impaired immunity.…”

Section: Discussionmentioning

confidence: 99%

Reliability of 7T¹H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation

Lally

Liu

Banerjee

et al. 2015

J. Magn. Reson. Imaging

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Purpose Evidence suggests that aberrant glutamatergic-signalling plays a role in numerous psychopathologies. To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy (1H-MRS) can non-invasively measure glutamatergic function. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. Materials and Methods At 7 T MR, we acquired 1H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (N = 26) twice on two separate days. An adapted echo time optimised point resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 parts per million, was used to excite and acquire the spectra. In house software was used to model glutamate, glutamine, and glutathione, amongst other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. Results Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥ 0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC > 0.62). A negative correlation was observed between glutathione concentration and age (r(24) = −0.37; P < .05), and a gender effect was noted on glutamine and glutathione. Conclusion The adapted sequence provides good reliability to measure glutamate, glutamine and glutathione signals.

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“…Mutations in other proteins implicated in pathogenesis might further predispose neurons to high levels of oxidative stress. For example, mutations in the chaperone protein VCP increase neuronal susceptibility to ROS build-up upon depletion of glutathione (GSH), a free radical scavenger which is also diminished in the motor cortices of ALS patients (Hirano et al 2014, Weiduschat et al 2014, Carrì et al 2015). Interestingly, GSH depletion in NSC34 cells has been shown to result in the formation of insoluble inclusions containing the hyperphosphorylated, truncated TDP-43 fragments commonly found in ALS histology (Iguchi et al 2012).…”

Section: Als and Ftld: When Aggregation Goes Awrymentioning

confidence: 99%

RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

Fan

Leung

2016

Advances in Experimental Medicine and Biology

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RNA granules are microscopically visible cellular structures that aggregate by protein–protein and protein-RNA interactions. Using stress granules as an example, we discuss the principles of RNA granule formation, which rely on the multivalency of RNA and multi-domain proteins as well as low-affinity interactions between proteins with prion-like/low-complexity domains (e.g. FUS and TDP-43). We then explore how dysregulation of RNA granule formation is linked to neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and discuss possible strategies for therapeutic intervention.

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Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique

Cited by 99 publications

References 31 publications

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Reliability of 7T¹H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation

RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

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Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique

Cited by 99 publications

References 31 publications

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Reliability of 7T1H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation

RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

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Reliability of 7T¹H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation