The expansion of a (G(4)C(2))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. (G(4)C(2))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 (G(4)C(2))(4) RNA and DNA not only complex tightly 
with heme but also enhance its intrinsic peroxidase and oxidase propensities. By 
contrast, the antisense (C(4)G(2))(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.