Integration of Micrornaome and Metabolomics to Dissect Cerebral Disease Progression in X-Linked Adrenoleukodystrophy
Singh J, Poisson L, and Giri S. Integration of Micrornaome and Metabolomics to Dissect Cerebral Disease Progression in X-Linked Adrenoleukodystrophy. J Neurochem 2019; 150:112.
Introduction: X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disease caused by mutations in peroxisomal ABCD1 gene. X-ALD males develop fatal cerebral demyelinating disease (ALD) the mechanism for which remains unknown. We took a novel multi-omics approach of untargeted metabolomics and next generation sequencing (HiSeq) to find regulatory (microRNA) and active (metabolite) pathways underlying the fatal neuroinflammation in ALD. Methods: Postmortem brain tissue from healthy controls and ALD patients were processed for microRNA (miRNA) and metabolite extraction and analysis. Data analysis was performed by "MetaboAnalyst 2.5" for GC-MS and Bioconductor for miRNA. Results: Each measured miRNA and metabolite was screened using appropriate ANOVA models. Thresholds for significance were set to control the estimated false discovery rate, per platform, at 5%. We compared postmortem brain white matter of healthy controls (CTL) with normal looking area (NLA) and periphery of plaque/lesion (PLS) regions within the ALD brain white matter. Analysis of variance (p < 0.05) and Post-hoc t-tests identified nineteen miRNA and eleven metabolites that significantly differed across the three groups (control, NLA and PLS). Of the nineteen miRNA seventeen were increased (PLS > NLA > CTL) and two were decreased (CTL > NLA > PLS). Seven metabolites were upregulated (PLS > NLA > CTL) and four were downregulated (CTL > NLA > PLS). We calculated the Pearson's correlation coefficient between the expression of these nineteen miRNA and the metabolite intensities of eleven metabolites for putative links between the global gene expression modulators (miRNAs), and metabolites. Conclusion: Our novel "transomic" modeling identifies, for the first time, integrated miRNA and metabolite pathways underlying demyelination in X-ALD.