Amyotrophic lateral sclerosis is a progressive and terminal neurodegenerative disease characterized by the selective degeneration of motor neurons within the motor cortex, brainstem and spinal cord. In the United States, approximately 14 cases of ALS are diagnosed each day and 30,000 people are living with the disease. The average time from disease onset to death is 3 years and no treatment that substantially 4-(Benzyloxy)phenol improves the clinical course of the disease is currently available. Proposed pathogenic mechanisms of ALS include oxidative stress, glutamate excitotoxicity, impaired axonal transport, neurotrophic deprivation, neuroinflammation, apoptosis, altered protein turnover, and mitochondrial dysfunction. Moreover, influences from astrocytes and microglia in the motor neuron microenvironment contribute to pathogenesis. In the last 20 years, a search for genetic factors has identified several genes associated with familial ALS and a few with sporadic ALS. Because fALS only accounts for 5�C10% of all cases of ALS, the causes leading to the vast majority of ALS are poorly understood. Environmental exposure to toxins, excessive physical activity, dietary factors, and changes in immunity increase the risk of developing sALS. These factors may drive epigenetic changes, which are well suited to explain disease onset and progression in sALS, as they may be acquired throughout life. Epigenetic modifications, including covalent modifications of DNA and histones as well as RNA editing, dynamically regulate gene expression without altering the genetic code. These modifications are important in chromosome integrity, cellular differentiation, development, and aging. Two such modifications, 5-methylcytosine and 5-hydroxymethylcytosine are associated with repression or activation of gene expression, respectively, in response to environmental and Folinic acid calcium salt pentahydrate developmental factors linked to age-related diseases. Although several genes have been implicated in the pathogenesis of ALS, the causes leading to most cases remain unknown. Environmental factors may be associated with the onset and development of sALS by altering epigenetic regulation. The aim of this study was to identify sALS-associated epigenetic marks resulting in aberrant gene expression. Abnormal 5mC patterns of repetitive elements such as Alu and LINE1, as well as altered function of methylation regulators such as the DNMTs, lead to changes in global 5mC or 5 HmC associated with neurodegeneration. We demonstrate increased global methylation in sALS spinal cord, perhaps due to an increase in DNMT activity. Furthermore, we report for the first time an increase in global 5 HmC in sALS spinal cord. Increased 5mC and 5 HmC may be due to 5mC providing more substrate for the TET proteins, TETs are not differentially expressed in spinal cord sALS according to our microarray data. TET should decrease the amount of 5mC only if 5mC is not increasing at a faster rate than the oxidation reaction. Although normal aging leads to increased global 5 HmC in mouse hippocampal DNA independently of increased levels of oxidative stress, in ALS, increased oxidative DNA damage and free radicals may contribute to global 5 HmC dysregulation. The base excision repair pathway responsible for oxidative DNA damage restoration and one of the active demethylation pathways, is deficient in ALS. Methylomics and transcriptomics analyses identified potential biologically relevant epigenes in postmortem sALS spinal cord. These epigenes were enriched with biological functions related to inflammation.