Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis

Chaves‐Filho, Adriano B.; Pinto, Isabella Fernanda Dantas; Dantas, Lucas S.; Xavier, André Machado; Inague, Alex; Faria, Rodrigo L.; Medeiros, Marisa Helena Gennari de; Glezer, Isaías; Yoshinaga, Marcos Y.; Miyamoto, Sayuri

doi:10.1038/s41598-019-48059-7

Cited by 114 publications

(126 citation statements)

References 69 publications

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“…LD accumulation has been observed in glial cells, including astrocytes, in early stages of neurodegeneration 46 . Recently, alterations in lipid metabolism (accumulation of cholesteryl esters, determined with lipidomic analysis) in spinal cords from SOD1 G93A transgenic mouse model have been reported that might be linked to astrogliosis and LD formation in astrocytes 48 , since a population of astrocytes isolated from the degenerating spinal cords of the same animal model exhibited significant abundance of LDs as well as autophagic and secretory vesicles, all characteristic features of cellular stress and inflammatory activation 70 . However, the mechanisms leading to increased LD accumulation in astrocytes are poorly understood and may, among others, rely on altered neuronal mitochondrial function and ROS as well as on astrocyte-neuron lactate shuttle 47 , in particular on astroglial lactate-derived lipid production in neurons and transfer of excess lipids in lipoprotein-like particles (ApoE) from neurons to astrocytes 47,71 .…”

Section: Discussionmentioning

confidence: 99%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca 2+ signaling and augments aerobic glycolysis with production of lactate, an important neuronal energy fuel. Astrocytes with cytoplasmic TDP-43 inclusions can cause motor neuron death, however, whether astroglial metabolism and metabolic support of neurons is altered in astrocytes with TDP-43 inclusions, is unclear. We measured lipid droplet and glucose metabolisms in astrocytes expressing the inclusion-forming C-terminal fragment of TDP-43 or the wild-type TDP-43 using fluorescent dyes or genetically encoded nanosensors. Astrocytes with TDP-43 inclusions exhibited a 3-fold increase in the accumulation of lipid droplets versus astrocytes expressing wild-type TDP-43, indicating altered lipid droplet metabolism. In these cells the noradrenaline-triggered increases in intracellular cAMP and Ca 2+ levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β 2-adrenergic receptors. Although noradrenaline triggered a similar increase in intracellular lactate levels in astrocytes with and without TDP-43 inclusions, the probability of activating aerobic glycolysis was facilitated by 1.6-fold in astrocytes with TDP-43 inclusions and lactate MCT1 transporters were downregulated. Thus, while in astrocytes with TDP-43 inclusions noradrenergic signaling is reduced, aerobic glycolysis and lipid droplet accumulation are facilitated, suggesting dysregulated astroglial metabolism and metabolic support of neurons in TDP-43-associated ALS and FTD. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of both upper and lower motor neurons in the brain and spinal cord, and by the progressive paralysis of voluntary muscles and death 1,2. The pathologic hallmark of ALS are cytoplasmic inclusions in motor neurons. In most cases (~95%) of sporadic and familial ALS, TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the key component of these inclusions 1-9. Moreover, TDP-43 has also been identified as the major protein in inclusions in frontotemporal dementia with ubiquitin-positive inclusions (FTD-U) 2,6. TDP-43 is a highly conserved protein (414 amino acids), ubiquitously expressed in all tissues and under physiological conditions, primarily localized to the nucleus; however, low levels are also present in the cytoplasm 2,3,8,10-13. TDP-43, an RNA-binding protein, is implicated in multiple aspects of RNA processing, including regulation of transcription, splicing, transport, and stabilization of mRNAs. It also regulates microRNA biogenesis and interacts with DNA. Therefore, its perturbance ...

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Section: Discussionmentioning

confidence: 99%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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“…31 Altered sphingolipids included sphingomyelins, sphingosines, ceramides and hexosylceramides, which have been previously reported in ALS participant plasma, 14 15 25 CSF, 8 and spinal cord, 32 33 and ALS mouse models. [32][33][34][35] Targeting sphingolipid metabolism with sphingolipid inhibitors is at the forefront of cancer therapeutics, 36 and has been advocated as a possible treatment for Alzheimer's, Parkinson's and Huntington's disease. 37 38 Our study provides evidence that sphingolipid metabolism may similarly be targeted in ALS as a potential therapeutic opportunity.…”

Section: Figurementioning

confidence: 99%

Untargeted metabolomics yields insight into ALS disease mechanisms

Goutman

Boss

Guo

et al. 2020

J Neurol Neurosurg Psychiatry

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ObjectiveTo identify dysregulated metabolic pathways in amyotrophic lateral sclerosis (ALS) versus control participants through untargeted metabolomics.MethodsUntargeted metabolomics was performed on plasma from ALS participants (n=125) around 6.8 months after diagnosis and healthy controls (n=71). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon rank-sum tests, adjusted logistic regression and partial least squares-discriminant analysis (PLS-DA), while group lasso explored sub-pathway-level differences. Adjustment parameters included sex, age and body mass index (BMI). Metabolomics pathway enrichment analysis was performed on metabolites selected by the above methods. Finally, machine learning classification algorithms applied to group lasso-selected metabolites were evaluated for classifying case status.ResultsThere were no group differences in sex, age and BMI. Significant metabolites selected were 303 by Wilcoxon, 300 by logistic regression, 295 by PLS-DA and 259 by group lasso, corresponding to 11, 13, 12 and 22 enriched sub-pathways, respectively. ‘Benzoate metabolism’, ‘ceramides’, ‘creatine metabolism’, ‘fatty acid metabolism (acyl carnitine, polyunsaturated)’ and ‘hexosylceramides’ sub-pathways were enriched by all methods, and ‘sphingomyelins’ by all but Wilcoxon, indicating these pathways significantly associate with ALS. Finally, machine learning prediction of ALS cases using group lasso-selected metabolites achieved the best performance by regularised logistic regression with elastic net regularisation, with an area under the curve of 0.98 and specificity of 83%.ConclusionIn our analysis, ALS led to significant metabolic pathway alterations, which had correlations to known ALS pathomechanisms in the basic and clinical literature, and may represent important targets for future ALS therapeutics.

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“…This homogenate was mixed with 400 μL of ice-cold methanol, containing 100 μM of butylated hydroxytoluene (BHT), and 100 μL of internal standards (10 µg/mL). 2 mL of chloroform: ethyl acetate (4:1) were added to the mixture, followed by vortexing during 30 s. After centrifugation at 1,500 x g for 2 min at 4°C, the lower phase containing total lipid extracts (TLE) was transferred to a new tube and dried under N 2 gas 63 . Dried TLE were dissolved in 100 µL of isopropanol and the UHPLC injection volume was set at 2 µL.…”

Section: Methodsmentioning

confidence: 99%

Distinct photooxidation-induced cell death pathways lead to selective killing of human breast cancer cells

Santos

Inague²,

Arini

et al. 2020

Preprint

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Lack of effective treatments for aggressive breast cancer is still a major global health problem. We previously reported that Photodynamic Therapy using Methylene Blue as photosensitizer (MB-PDT) massively kills metastatic human breast cancer, marginally affecting healthy cells. In this study we aimed to unveil the molecular mechanisms behind MB-PDT effectiveness. Through lipidomic and biochemical approaches we demonstrated that MB-PDT efficiency and specificity relies on polyunsaturated fatty acids-enriched membranes and on the better capacity to deal with photooxidative damage displayed by non-tumorigenic cells. We found out that, in tumorigenic cells, lysosome membrane permeabilization is accompanied by ferroptosis and/or necroptosis. Our results broadened the understanding of MB-PDT-induced photooxidation mechanisms and specificity in breast cancer cells. Therefore, we demonstrated that efficient approaches could be designed on the basis of lipid composition and metabolic features for hard-to-treat cancers. The results further reinforce MB-PDT as a therapeutic strategy for highly aggressive human breast cancer cells.

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Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis

Cited by 114 publications

References 69 publications

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Untargeted metabolomics yields insight into ALS disease mechanisms

Distinct photooxidation-induced cell death pathways lead to selective killing of human breast cancer cells

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