Plasma metabolome and skin proteins in Charcot-Marie-Tooth 1A patients

Soldevilla, Beatriz; Cuevas-Martín, Carmen; Ibáñez, Clara; Santacatterina, Fulvio; Alberti, M.; Simó, Carolina; Casasnovas, Carlos; Márquez-Infante, Celedonio; Sevilla, Teresa; Pascual, Samuel Ignacio Pascual; Sánchez‐Aragó, María; Espinós, Carmen; Palau, Francesc; Cuezva, José M.

doi:10.1371/journal.pone.0178376

Cited by 13 publications

(13 citation statements)

References 49 publications

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“…Likewise, GDAP1 mutations lead to defective mitochondrial complex I activity and oxidative stress ( 20 , 21 ). Consistent with these observations, loss of mitochondrial and antioxidant proteins have been reported in skin biopsies of CMT patients ( 22 ) and in peripheral nerves of the Gdap1 knock-out mouse ( Gdap1 -null) ( 15 ), further suggesting that mitochondrial function and oxidative stress provide potential targets to treat CMT disease.…”

Section: Introductionsupporting

confidence: 60%

“…4A ). The reduction of epidermal nerve density is a common neuropathic abnormality observed in skin biopsies of CMT patients ( 27 ) that is accompanied by loss of the mitochondrial proteins involved in OXPHOS and scavenging ROS ( 22 ). Not surprisingly, fibroblasts of patients with GDAP1 dominant mutations show enhanced ROS production ( 21 ), as we have observed in knockdown SH-SY5Y cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease

Nuevo‐Tapioles

Santacatterina

Sánchez-Garrido

et al. 2021

Human Molecular Genetics

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Charcot–Marie-Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degeneration of nerves in skin biopsies of CMT patients. Herein, we followed a drug-repurposing approach to find drugs in an FDA-approved library that could prevent development of CMT disease in the Gdap1-null mouse model. We found that the antibiotic florfenicol is a mitochondrial uncoupler that prevents the production of reactive oxygen species and activates respiration in human GDAP1-knockdown neuroblastoma cells and in dorsal root ganglion neurons of Gdap1-null mice. Treatment of CMT-affected Gdap1-null mice with florfenicol has no beneficial effect in the course of the disease. However, administration of florfenicol, or the antioxidant MitoQ to pre-symptomatic GDAP1-null mice prevented weight gain and ameliorated the motor coordination deficiencies that developed in the Gdap1-null mice. Interestingly, both florfenicol and MitoQ halted the decay in mitochondrial and redox proteins in sciatic nerves of Gdap1-null mice supporting that oxidative damage is implicated in the etiology of the neuropathy. These findings support the development of clinical trials for translation of these drugs for treatment of CMT patients.

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Section: Introductionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease

Nuevo‐Tapioles

Santacatterina

Sánchez-Garrido

et al. 2021

Human Molecular Genetics

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“…To date, transcriptional biomarkers in skin biopsies of experimental and human CMT1A have been proposed, demonstrating that disease severity can be related to cutaneous mRNA expression ( 14 , 95 ). Moreover, a study performed on the plasma of CMT1A patients highlighted an increase of protein catabolism and the mobilization of membrane lipids involved in inflammatory signaling as further potential sources of biomarkers ( 96 ). Nevertheless, we are still far from having reliable and clinically acceptable disease severity biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A

et al. 2020

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In Charcot–Marie–Tooth type 1A (CMT1A), Schwann cells exhibit a preponderant transcriptional deficiency of genes involved in lipid biosynthesis. This perturbed lipid metabolism affects the peripheral nerve physiology and the structure of peripheral myelin. Nevertheless, the identification and functional characterization of the lipid species mainly responsible for CMT1A myelin impairment currently lack. This is critical in the pathogenesis of the neuropathy since lipids are many and complex molecules which play essential roles in the cell, including the structural components of cellular membranes, cell signaling, and membrane trafficking. Moreover, lipids themselves are able to modify gene transcription, thereby affecting the genotype–phenotype correlation of well-defined inherited diseases, including CMT1A. Here we report for the first time a comprehensive lipid profiling in experimental and human CMT1A, demonstrating a previously unknown specific alteration of sphingolipid (SP) and glycerophospholipid (GP) metabolism. Notably, SP, and GP changes even emerge in biological fluids of CMT1A rat and human patients, implying a systemic metabolic dysfunction for these specific lipid classes. Actually, SP and GP are not merely reduced; their expression is instead aberrant, contributing to the ultrastructural abnormalities that we detailed by X-ray diffraction in rat and human internode myelin. The modulation of SP and GP pathways in myelinating dorsal root ganglia cultures clearly sustains this issue. In fact, just selected molecules interacting with these pathways are able to modify the altered geometric parameters of CMT1A myelinated fibers. Overall, we propose to exploit the present SP and GP metabolism impairment to select effective drugs and validate a set of reliable biomarkers, which remain a challenge in CMT1A neuropathy.

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“…The identification of biomarkers like GDF-15 in the transcriptome of skeletal muscle from TK2-associated patients raises the possibility of metabolic fingerprinting for mitochondrial diseases [ 78 ]. Metabolic signatures identified for muscular dystrophies and Charcot-Marie-Tooth disease type 1A could be used to indicate disease severity and aid diagnosis [ 79 , 80 , 81 ].…”

Section: Multi-omics Approachesmentioning

confidence: 99%

The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

Yubero

Benito

Pijuan

et al. 2021

IJMS

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The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives.

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Plasma metabolome and skin proteins in Charcot-Marie-Tooth 1A patients

Cited by 13 publications

References 49 publications

Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease

Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A

The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

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