Epigenetics in Friedreich's Ataxia: Challenges and Opportunities for Therapy

Abstract

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by homozygous expansion of a GAA·TTC trinucleotide repeat within the first intron of the FXN gene, leading to reduced FXN transcription and decreased levels of frataxin protein. Recent advances in FRDA research have revealed the presence of several epigenetic modifications that are either directly or indirectly involved in this FXN gene silencing. Although epigenetic marks may be inherited from one generation to the next, modifications of DNA and histones can be reversed, indicating that they are suitable targets for epigenetic-based therapy. Unlike other trinucleotide repeat disorders, such as Huntington disease, the large expansions of GAA·TTC repeats in FRDA do not produce a change in the frataxin amino acid sequence, but they produce reduced levels of normal frataxin. Therefore, transcriptional reactivation of the FXN gene provides a good therapeutic option. The present paper will initially focus on the epigenetic changes seen in FRDA patients and their role in the silencing of FXN gene and will be concluded by considering the potential epigenetic therapies.

Friedreich Ataxia Patient Tissues Exhibit Increased 5-Hydroxymethylcytosine Modification and Decreased CTCF Binding at the FXN Locus

“…Secondly, there is evidence that GAA repeat expansions can induce heterochromatin-mediated gene silencing effects [12]. Consistent with the latter hypothesis, several FRDA-related epigenetic changes have been identified in the immediate vicinity of the expanded GAA repeats of the FXN gene [13]. An initial investigation of DNA methylation of the FXN gene by bisulfite sequencing revealed hypermethylation of the cytosine residue of specific CpG sites upstream of the GAA repeat sequence in FRDA patient lymphoblastoid cells compared to cells derived from unaffected individuals [14].…”

Epigenetic-based therapies for Friedreich ataxia

“…Such histone modifications have now been identified within the FXN gene in FRDA cells, tissues, and mouse models, predominantly at the region immediately upstream of the expanded GAA repeats, indicating that the FXN gene is subject to heterochromatin silencing (Sandi et al, 2013) (Table 1, Figure 1). Histone modifications at the FXN locus were first identified by Gottesfeld and colleagues, who reported lower levels of several acetylated H3 and H4 lysine residues, together with increased H3K9me2 and H3K9me3 in the upstream GAA regions of FRDA lymphoblastoid cells (Herman et al, 2006).…”

“…Therefore, compounds which can reduce H3K9me2 levels are an attractive option where gene silencing involves increased H3K9me2 levels, as seen with FRDA (Sandi et al, 2013) (Table 1). This has led to the development of various compounds that can inhibit the G9a activity directly or indirectly.…”

Epigenetics of Alzheimer's Disease and Frontotemporal Dementia

“…In FTD and AD, genes such as GRN, BDNF, cyclic adenosine monophosphate response element-binding protein, and C9ORF72, are hypermethylated and repressed, possibly contributing to the pathogenicity of the disease, and are potential targets for DNMTi-based therapies. A study in Friedreich ataxia, an autosomal recessive disease, used DNMTi to reverse the hypermethylation associated with a trinucleotide repeat expansion at the FXN locus; the study revealed a modest effect in mouse cells, but the treatment was ineffective in human Friedreich ataxia cells (reviewed in [88]). However, cell lines derived from fragile X patients showed beneficial effects of 5-azadeoxycytidine treatment [89].…”