Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications

Abstract

Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.

The ‘golden age’ of DNA methylation in neurodegenerative diseases

“…Another gene involved in a form of ataxia, the spinocerebellar ataxia type 2 (SCA2), is the ataxin-2 ( ATXN2 ) gene; the CAG repeat in the mutant gene only partially accounts for the wide range of observed age of onset. It was demonstrated that DNA methylation might regulate the expression of the mutant gene modulating the onset and the severity of the disease [ 76 ]. Since this gene is also involved in Parkinson ' s disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration, it is highly probable that at least a part of the epigenetic contribution hypothesized for these diseases can be attributable to the methylation pattern of the ATXN2 gene.…”

Quantitative Profiling and Identification of Plasma Proteins of Spinocerebellar Ataxia Type 2 Patients

“…Mutated ataxin-2 protein has been shown to alter the activity of calcium channels in Purkinje cells of brain and thus causing their death via apoptosis [13]. Moreover, hypermethylation of the promoter region of the ataxin-2 gene was also found to be associated with the pathogenic expansion of CAG repeats and the onset of SCA2 [14]. …”

Welcome to the 10th volume of Epigenomics

“…The ATXN2 promoter contains a CpG island rich segment without a TATA box. Both hyper-and hypomethylation states are found in the ATXN2 promoter in SCA2 patients [69,70]. In SCA1, local DNA methylation patterns have been detected at ATXN1 locus.…”

“…Confounding by genetics or shared mother-child environmental factors is a particular concern that should be addressed. For example, paternal alcohol consumption could be employed as a 'negative control' that will share the same confounding structure as maternal alcohol consumption but cannot plausibly affect offspring DNA methylation through a direct causal intrauterine mechanism [70]. Techniques such as two-step Mendelian randomization [71] could also be applied to explore the causal effect of prenatal alcohol exposure on DNA methylation and the causal effect of DNA methylation on offspring outcomes.…”