Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

Cassina, Patricia; Miquel, Ernesto; Martínez-Palma, Laura; Cassina, Adriana

doi:10.1159/000516926

Cited by 18 publications

(23 citation statements)

References 107 publications

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“…Mitochondrial dysfunction associated with metabolism deregulation is a known pathological actor in ALS [ 83 , 84 , 85 , 86 , 87 ]. As confirmed by the present study, alterations in levels of several amino acids in samples from ALS patients highlighted a change in amino acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

et al. 2022

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Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA < 0.035) and revealed an excellent discriminant profile for muscle metabolome (p-CV-ANOVA < 0.0012). Citramalate was discriminant for both muscle and serum. High lauroylcarnitine levels in muscle were associated with low Forced Vital Capacity. Transcriptomics analysis of key antioxidant enzymes showed an upregulation of SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients.

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Section: Discussionmentioning

confidence: 99%

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

et al. 2022

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“…Microglia can adopt a toxic M1 phenotype or a neuroprotective M2 phenotype [126][127][128] . In mutant SOD1-transgenic mice, the microglia switched from the M2 to the M1 phenotype after disease onset 129 .…”

Section: Boxmentioning

confidence: 99%

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Mead

Shan²,

Reiser³

et al. 2022

Nat Rev Drug Discov

141

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Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10–15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

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“…Several genes have been identified as causative or disease-modifying fALS and sALS, such as C9ORF72, SOD1, TARDBP, and FUS. D1 is the most studied gene mutation in ALS disease and one of the essential antioxidant enzymes involved in redox sensing, oxidative stress metabolism, and signal transduction (Jawaid et al, 2010;Gill et al, 2019;Cassina et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Impact of the Amyotrophic Lateral Sclerosis Disease on the Biomechanical Properties and Oxidative Stress Metabolism of the Lung Tissue Correlated With the Human Mutant SOD1G93A Protein Accumulation

Aydemir

Malik

Kulaç

et al. 2022

Front. Bioeng. Biotechnol.

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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, and ALS incidence is increasing worldwide. Patients with ALS have respiratory failure at the disease’s end stages, leading to death; thus, the lung is one of the most affected organs during disease progression. Tissue stiffness increases in various lung diseases because of impaired extracellular matrix (ECM) homeostasis leading to tissue damage and dysfunction at the end. According to the literature, oxidative stress is the major contributor to ECM dysregulation, and mutant protein accumulation in ALS have been reported as causative to tissue damage and oxidative stress. In this study, we used SOD1G93A and SOD1WT rats and measured lung stiffness of rats by using a custom-built stretcher, where H&E staining is used to evaluate histopathological changes in the lung tissue. Oxidative stress status of lung tissues was assessed by measuring glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), catalase (CAT), and superoxide dismutase 1 (SOD1) levels. Western blot experiments were performed to evaluate the accumulation of the SOD1G93A mutated protein. As a result, increased lung stiffness, decreased antioxidant status, elevated levels of oxidative stress, impaired mineral and trace element homeostasis, and mutated SOD1G93A protein accumulation have been found in the mutated rats even at the earlier stages, which can be possible causative of increased lung stiffness and tissue damage in ALS. Since lung damage has altered at the very early stages, possible therapeutic approaches can be used to treat ALS or improve the life quality of patients with ALS.

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Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

Cited by 18 publications

References 107 publications

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Impact of the Amyotrophic Lateral Sclerosis Disease on the Biomechanical Properties and Oxidative Stress Metabolism of the Lung Tissue Correlated With the Human Mutant SOD1G93A Protein Accumulation

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