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Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease.

ABSTRACT: Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries a significant risk of morbidity and mortality. Accurate presymptomatic diagnosis is therefore critical to facilitate the efficacy of existing transplant approaches and to avoid unnecessary treatment of children who will not develop KD. Unfortunately, current diagnostic criteria, including GALC activity, genetic analysis, and psychosine measurement, are insufficient for secure presymptomatic diagnosis. This study performs a global metabolomic analysis to identify pathogenetic metabolic pathways and novel biomarkers implicated in the authentic mouse model of KD known as twitcher. At a time point before onset of signs of disease, twitcher hindbrains had metabolic profiles similar to WT, with the exception of a decrease in metabolites related to glucose energy metabolism. Many metabolic pathways were altered after early signs of disease in the twitcher, including decreased phospholipid turnover, restricted mitochondrial metabolism of branched-chain amino acids, increased inflammation, and changes in neurotransmitter metabolism and osmolytes. Hypoxanthine, a purine derivative, is increased before signs of disease appear, suggesting its potential as a biomarker for early diagnosis of KD. Additionally, given the early changes in glucose metabolism in the pathogenesis of KD, diagnostic modalities that report metabolic function, such as positron emission tomography, may be useful in KD. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Weinstock NI

PROVIDER: S-EPMC5027975 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease.

Weinstock Nadav I NI Wrabetz Lawrence L Feltri M Laura ML Shin Daesung D

Journal of neuroscience research 20161101 11

Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries ...[more]

PMID: 27638595

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Project description:BackgroundHeart failure (HF) is the most common cause of morbidity and mortality in developed countries. Here, we identify biologically relevant transcripts that are significantly altered in the early phase of myocardial infarction and are associated with the development of post-myocardial infarction HF.MethodsWe collected peripheral blood samples from patients with ST-segment elevation myocardial infarction (STEMI): n = 111 and n = 41 patients from the study and validation groups, respectively. Control groups comprised patients with a stable coronary artery disease and without a history of myocardial infarction. Based on plasma NT-proBNP level and left ventricular ejection fraction parameters the STEMI patients were divided into HF and non-HF groups. Microarrays were used to analyze mRNA levels in peripheral blood mononuclear cells (PBMCs) isolated from the study group at four time points and control group. Microarray results were validated by RT-qPCR using whole blood RNA from the validation group.ResultsSamples from the first three time points (admission, discharge, and 1 month after AMI) were compared with the samples from the same patients collected 6 months after AMI (stable phase) and with the control group. The greatest differences in transcriptional profiles were observed on admission and they gradually stabilized during the follow-up. We have also identified a set of genes the expression of which on the first day of STEMI differed significantly between patients who developed HF after 6 months of observation and those who did not. RNASE1, FMN1, and JDP2 were selected for further analysis and their early up-regulation was confirmed in HF patients from both the study and validation groups. Significant correlations were found between expression levels of these biomarkers and clinical parameters. The receiver operating characteristic (ROC) curves indicated a good prognostic value of the genes chosen.ConclusionsThis study demonstrates an altered gene expression profile in PBMCs during acute myocardial infarction and through the follow-up. The identified gene expression changes at the early phase of STEMI that differentiated the patients who developed HF from those who did not could serve as a convenient tool contributing to the prognosis of heart failure.

Dataset Information

Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease.

Publications

Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease.

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