Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset

Abstract

ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [(3)H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

“…Elevation in global levels of DNA methylation has been reported in Alzhei­mer’s disease blood [65] but not in other tissue types, such as the entorhinal cortex [66], where a decrease in global hydroxymethylation was previously reported [67]. Studies in ALS have also reported increased global DNA methylation, both in the spinal cord [15] and blood samples [16] of sALS patients, but their results regarding global DNA methylation detectable in blood have been conflicting. Here, we aimed to conclude these disputes by overcoming the shortcomings of previous studies, such as small cohort sizes and biases towards the age of onset by screening a large and heterogeneous cohort of ALS patients ( n = 267), including sALS, C9orf72+ ALS, and fALS.…”

“…More recent studies have reported an increase in 5-mC levels detectable in blood samples of sALS patients [16], and some have suggested abnormalities in the regulatory machinery which takes part in the maintenance of DNA methylation [17, 18]. Alongside holistic methylation studies, others have focused on the methylation status of the C9orf72 gene promoter, shown to be hypermethylated in expansion carrier ALS and FTD patients [19-22].…”

“…By using an ELISA-based assay, one study reported a significant increase in global 5-mC levels in spinal cord samples of sALS patients, but not in the blood [15], whereas another study, using an HPLC-based assay, reported an increase in global 5-mC in blood [16]. This motivated us to further investigate global 5-mC levels in different subtypes of ALS and other NDDs, including SCA1 and SCA2, HD, FRDA, and DM1 (Table 1).…”

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

“…Recently, several studies have reported aberrant DNA methylation in ALS patients (Tremolizzo et al 2014;Belzil et al 2014;Xi et al 2013). Previously, we reported that BM-MSCs from ALS patients have diminished stem cell capacity due to decreased secretion of numerous trophic/growth factors (Cho et al 2010b).…”

“…In ALS patients, increased expression of DNMT1 and DNMT3A has been observed in motor cortex tissues and spinal cord motor neurons (Chestnut et al 2011). Elevated global DNA methylation was also observed in the whole blood of ALS patients (Tremolizzo et al 2014;Xi et al 2013). Not unlike progressive degenerative diseases, cellular senescence is brought on by increased epigenetic modifications, driving DNA methylation-induced formation of senescence-associated heterochromatin foci (Johnson et al 2012;Bork et al 2010;So et al 2011;Kosar et al 2011); this suggests that there may be a symptomatic correlation between cellular senescence and degenerative diseases, like ALS, at the epigenetic level.…”