Abstract
The expansion of a (G4C2)n repeat within the human C9orf72 gene has been causally linked to a number of neurodegenerative diseases, most notably familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies have shown that the repeat expansion alters gene function in four ways, disrupting the gene's normal cellular roles and introducing toxic gain of function at the level of both DNA and RNA. (G4C2)n DNA, as well as the RNA transcribed from it, are found to fold into four-stranded G-quadruplex structures. It has been shown that the toxicity of the RNA G-quadruplexes, often localized in intracellular RNA foci, lies in their ability to sequester many important RNA binding proteins. Herein we propose that a distinct toxic property of such RNA and DNA G-quadruplexes from the C9orf72 gene may arise from their ability to bind and oxidatively activate cellular heme. We show that G-quadruplexes formed by both (G4C2)4 RNA and DNA not only complex tightly with heme but also enhance its intrinsic peroxidase and oxidase propensities. By contrast, the antisense (C4G2)4 RNA and DNA neither bind heme nor influence its oxidative activity. Curiously, the ability of C9orf72 DNA and transcripts to bind and activate heme mirror similar properties that have been reported for the Aβ peptide and its oligomers in Alzheimer's disease neurons. It is therefore conceivable that C9orf72 RNA G-quadruplex tangles play roles in sequestering intracellular heme and promoting oxidative damage in ALS and FTD analogous to those proposed for Aβ peptide and its tangles in Alzheimer's Disease. Given that neurodegenerative diseases in general are characterized by mitochondrial and respiratory malfunctions, the role of C9orf72 DNA and RNA in heme sequestration as well as its inappropriate activation in ALS and FTD neurons may warrant examination.
Highlights
Amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease) and frontotemporal dementia (FTD) are both serious and significant neurological diseases that appear to have familial forms as well as arising sporadically within populations [1]
Given that in C9orf72-impacted diseases both the DNA and RNA corresponding to the hexanucleotide repeat expansion fold into G-quadruplexes, we investigated whether such G-quadruplexes bound heme, concomitantly activating the bound heme towards accelerated oxidative activity
A major underpinning of the postulated gain of function by the repeat expanded C9orf72 gene in familial amyotrophic lateral sclerosis (ALS) and FTD is the formation of G-quadruplexes by the G-rich transcript
Summary
Amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease) and frontotemporal dementia (FTD) are both serious and significant neurological diseases that appear to have familial forms as well as arising sporadically within populations [1]. An abnormal expansion of a repeating GGGGCC sequence in the DNA of the C9orf gene was identified in patients with the familial forms of these diseases, and in a proportion of patients with the sporadic diseases [1,2,3]. It was proposed that both gain-of-function and loss-of-function toxicity could be linked to repeat expansion within C9orf, at the level of gene (DNA) as well as transcript (RNA). Given that in C9orf72-impacted diseases both the DNA and RNA corresponding to the hexanucleotide repeat expansion fold into G-quadruplexes, we investigated whether such G-quadruplexes bound heme, concomitantly activating the bound heme towards accelerated oxidative activity
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