Abstract
Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive and terminal neurodegenerative disease characterized by the selective degeneration of motor neurons within the motor cortex, brainstem and spinal cord [1]
Several genes have been implicated in the pathogenesis of ALS, the causes leading to most cases remain unknown
The aim of this study was to identify sALS-associated epigenetic marks resulting in aberrant gene expression
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive and terminal neurodegenerative disease characterized by the selective degeneration of motor neurons within the motor cortex, brainstem and spinal cord [1]. In the United States, approximately 14 cases of ALS are diagnosed each day and 30,000 people are living with the disease. Influences from astrocytes and microglia in the motor neuron microenvironment contribute to pathogenesis [3]. In the last 20 years, a search for genetic factors has identified several genes associated with familial ALS (fALS) and a few with sporadic ALS (sALS) [4,5,6]. Because fALS only accounts for 5–10% of all cases of ALS, the causes leading to the vast majority of ALS (sALS) are poorly understood [1]
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