Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

Szelechowski, Marion; Amoêdo, Nívea Dias; Obre, Émilie; Léger, Cécile; Allard, Louise; Bonneu, Marc; Claverol, Stéphane; Lacombe, Didier; Oliet, Stéphane H. R.; Chevallier, S.; Masson, Gwendal Le; Rossignol, Rodrigue

doi:10.1038/s41598-018-22318-5

Cited by 68 publications

(59 citation statements)

References 63 publications

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“…In our studies, fibroblasts are grown in medium with a high glucose level, meaning that the high respiration rate observed in fALS cells might be explained by disturbances in glycolysis. It was shown that components of the glycolysis pathway were lower in ALS patients' skin fibroblasts than in controls (69). The high respiration rate in fALS fibroblasts might also be a compensation effect in response to their low DC m .…”

Section: Discussionmentioning

confidence: 95%

Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics

et al. 2018

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Bioenergetic failure, oxidative stress, and changes in mitochondrial morphology are common pathologic hallmarks of amyotrophic lateral sclerosis (ALS) in several cellular and animal models. Disturbed mitochondrial physiology has serious consequences for proper functioning of the cell, leading to the chronic mitochondrial stress. Mitochondria, being in the center of cellular metabolism, play a pivotal role in adaptation to stress conditions. We found that mitochondrial dysfunction and adaptation processes differ in primary fibroblasts derived from patients diagnosed with either sporadic or familial forms of ALS. The evaluation of mitochondrial parameters such as the mitochondrial membrane potential, the oxygen consumption rate, the activity and levels of respiratory chain complexes, and the levels of ATP, reactive oxygen species, and Ca2+ show that the bioenergetic properties of mitochondria are different in sporadic ALS, familial ALS, and control groups. Comparative statistical analysis of the data set (with use of principal component analysis and support vector machine) identifies and distinguishes 3 separate groups despite the small number of investigated cell lines and high variability in measured parameters. These findings could be a first step in development of a new tool for predicting sporadic and familial forms of ALS and could contribute to knowledge of its pathophysiology.—Walczak, J., Dębska‐Vielhaber, G., Vielhaber, S., Szymański, J., Charzyńska, A., Duszyński, J., Szczepanowska, J. Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics. FASEB J. 33, 4388–4403 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 95%

Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics

et al. 2018

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“…Unlike other studies of the whole plasma proteome in ALS, here we show that the protein composition of plasma CPA from ALS individuals reproduces most of the extensively described pathological hallmarks of ALS, including pathways involved in protein degradation through the proteasome and energy metabolism ( 52-55 ). The same approach applied to the TMT-proteomic datasets reveals regulated features also known to be involved in ALS pathology and in protein aggregates homeostasis including lysosome as well as lipoprotein and glycosaminoglycan metabolisms ( 33,34,45,48,49,(52)(53)(54)(55) ) (Table S4). All disease-related alterations in proteasome activity in ALS have so far been shown in such detail only in brain, spinal cord and in neuronal cell lines, but not systemically or more specifically in blood, as in our study ( 52,53 ).…”

Section: Discussionmentioning

confidence: 99%

“…Within the top ten regulated pathways, five were involved in metabolism of lipoproteins (Table S4). The significant representation of these pathways in our brain/CPA proteomes reflects known changes of the ALS pathophysiology, where metabolism is thought to be switched from sugars and carbohydrates to lipids use ( [33][34][35] ). To identify potential protein candidates for biomarkers analysis, we looked at highly regulated protein (unique peptides ≥ 2, LogFC < -0.693 or > 0.693, p-value < 0.05; 48 proteins in total) within the 69 pathways highlighted by FAT.…”

Section: Functional Analysismentioning

confidence: 99%

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

Adiutori

Puentes

Bremang

et al. 2020

Preprint

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Blood-based biomarkers can be informative of brain disorders where protein aggregation play a major role. The proteome of plasma and circulating protein aggregates (CPA) reflect the inflammatory and metabolic state of the organism and can be predictive of system-level and/or organ-specific pathologies. CPA are enriched with heavy chain neurofilaments (NfH), key axonal constituents involved in brain aggregates formation and biomarkers of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Here we show that CPA and brain protein aggregates (BPA) from ALS differ in protein composition and appear as a combination of electron-dense large globular and small filamentous formations on transmission electron microscopy. CPA are highly enriched with proteins involved in the proteasome and energy metabolism. Compared to the human proteome, proteins within aggregates show distinct and tissue-dependent chemical features of aggregation propensity. The use of a TMTcalibrator™ proteomics workflow with ALS brain as calibrant reveals 4973 brain-derived low-abundance proteins in CPA, including the products of translation of 24 ALS risk genes. 285 of these (5.7%) are regulated in ALS CPA including FUS (p<0.05). CPA from both ALS and healthy controls affect cell viability when testing endothelial and PC12 neuronal cell lines, while CPA from ALS exert a more toxic effect at lower concentrations. The analysis of resistance to protease enzymes hydrolysis indicates an ALS-specific digestion pattern for NfH using enterokinase. This study reveals how peripheral protein aggregates are significantly enriched with brain proteins which are highly representative of ALS pathology and a potential alternative source of biomarkers and therapeutic targets for this incurable disorder.Significance StatementMolecular mechanism of neurodegeneration like protein aggregation are important brain-specific alterations which need to be addressed therapeutically. Recently described fluid biomarkers of neurodegenerative disorders provide means for stratification and monitoring of disease progression. Here we show that circulating protein aggregates are easily accessible in blood and reproduce important features of brain pathology for an incurable disorder like amyotrophic lateral sclerosis. They represent a source of biomarkers and of novel therapeutics for ALS.

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“…Microarray analysis and proteomics studies also provided evidence for a disturbed carbohydrate metabolism in ALS. Indeed, several studies explored the downregulation of glycolysis components in ALS patients, including the key enzymes phosphoglucomutase 2 like 1 and phosphoglycerate kinase [23,43]. Consistently, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) mRNA was found to be reduced in the post-mortem cortex of ALS patients [44].…”

Section: Introductionmentioning

confidence: 96%

“…Indeed, both fALS and sporadic ALS (sALS) patients exhibit decreased weight and fat depots, which could be the result of a combined decrease in energy uptake, for example, due to a loss in appetite, and an increase in energy expenditure [17][18][19][20]. While dysbalanced energy homeostasis is an early event in ALS rodent models [21][22][23][24], it remains to be determined whether this is a primary or secondary event in ALS patients [4].…”

Section: Introductionmentioning

confidence: 99%

Existing and Emerging Metabolomic Tools for ALS Research

Germeys

Vandoorne

Bercier

et al. 2019

Genes

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Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new possibilities for ALS research. Here, we review existing and emerging metabolomic tools that could be used to further investigate the role of metabolism in ALS. A better understanding of the metabolic state of motor neurons and their surrounding cells could hopefully result in novel therapeutic strategies.

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Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

Cited by 68 publications

References 63 publications

Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics

Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

Existing and Emerging Metabolomic Tools for ALS Research

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