The 5’-Untranslated Region of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-Aconitase Iron-Responsive Element; Novel Therapies for Amytrophic Lateral SclerosisReport as inadecuate




The 5’-Untranslated Region of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-Aconitase Iron-Responsive Element; Novel Therapies for Amytrophic Lateral Sclerosis - Download this document for free, or read online. Document in PDF available to download.

The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame C9orf72 is a frequent cause of amyotrophic lateral sclerosis ALS and frontotemporal dementia FTD. Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region UTR of the messenger RNA encoding C9orf72 with the iron responsive elements IRE that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides ASO have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.

KEYWORDS

Amyotrophic Lateral Sclerosis ALS, Iron-Responsive Element IRE, C9orf72 mRNA, Mitochondrial Aconitase mACO, Frontotemporal Dementia FTD, Amyloid Precursor Protein APP, HIV Trans-Activation Response Element TAR, Antisense Oligonucleotides ASO, Iron-Regulatory Proteins-1 and -2 IRP1 and IRP2

Cite this paper

A. Lu, M. , Rajanala, S. , Mikkilineni, S. , Cahill, C. , Brown, R. , D. Berry, J. and Rogers, J. 2016 The 5’-Untranslated Region of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-Aconitase Iron-Responsive Element; Novel Therapies for Amytrophic Lateral Sclerosis. Neuroscience and Medicine, 7, 15-26. doi: 10.4236-nm.2016.71003.





Author: Monica A. Lu1, Susruthi Rajanala1, Sohan V. Mikkilineni1, Catherine M. Cahill1, Robert Brown2, James D. Berry3, Jack T. Rogers1

Source: http://www.scirp.org/



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