Dataset Information

High-resolution map of copy number variations in motor cortex of Control and Sporadic Amyotrphic Lateral Sclerosis patients by using a customized exon-centric comparative genomic hybridization array.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole transcriptome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed genomic structural aberrations occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, which might represent novel potential biomarkers and therapeutic targets. This study represents the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107375 | GEO | 2018/12/31

REPOSITORIES: GEO

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Project description:Knowledge about the nature and timepoint of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis (ALS) is largely lacking. It could not only pave the way for valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs (miRNAs) are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained expression profiles of miRNAs as well as other non-coding RNAs (ncRNAs) in the serum of sporadic ALS patients (sALS), familial ALS cases (fALS), asymptomatic mutation carriers and healthy controls. We observed a strikingly homogenous ncRNA profile in fALS patients that, to a large extend, was independent to the underlying disease gene and different to heterogeneous ncRNA signatures in sALS patients. Moreover, we identified 68 significantly dysregulated ncRNAs in pre-manifest ALS mutation carriers, more than 20 years before the estimated time window of disease onset. 91% of ncRNA alterations in mutation carriers overlapped with the fALS patients revealing progressive changes towards and during the disease. Our data thus demonstrate a high epigenetic heterogeneity amongst sALS patients and suggest common denominators regarding molecular pathogenesis of different ALS genes. We describe the earliest pathomolecular alterations in ALS known to date, which provide a basis for the development of predictors of disease onset as well as the discovery of novel therapeutic targets and strongly argue for studies evaluating pre-symptomatic disease-modifying treatment in ALS. Serum ncRNA pofiles of sporadic and familiar ALS patients as well as asymptomatic ALS mutation carriers were compared to age and gender matched healthy controls using a total of 53 Affymetrix miRNA 3.0 arrays. In detail, a total of 9 fALS patients (analyzed in 6 arrays) were compared to 10 controls, a total of 18 ALS mutation carriers (analyzed in 12 arrays) were compared to 8 controls and 18 sALS patients were compared to 16 controls.

Dataset Information

High-resolution map of copy number variations in motor cortex of Control and Sporadic Amyotrphic Lateral Sclerosis patients by using a customized exon-centric comparative genomic hybridization array.

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