. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. 2013 Mar;125(3):413-23. PubMed.


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  1. In less than a week, two publications reveal the existence of a relatively obscure process of translation—repeat-associated non-ATG (RAN) translation in C9ORF72-associated ALS and FTD. RAN translation has already been shown in two other repeat-associated diseases, myotonic dystrophy type 1 and spinocerebellar ataxia 8, where the extended three-nucleotide repeats in the RNA have been shown to form a hairpin loop, which initiates translation and synthesis of homopolymeric repeats in all three reading frames. Both groups hypothesized that the C9ORF72 GGGGCC repeat forms a similar hairpin loop, which then initiates RAN translation and generates dipeptide repeats (DPRs) in all three frames (GA)n, (GP)n, and (GR)n. They generated antibodies to the three DPRs and, following validation, both groups showed that DPRs colocalize with p62-positive, TDP-43-negative inclusions, which have been proposed as a hallmark of C9ORF72-associated pathology (Al-Sarraj et al., 2011). As such, the strongest signals have been found in the cerebellum and hippocampus, although DPR aggregates are reported in disease-relevant regions as well, i.e., frontal and temporal cortex. The lack of colocalization with TDP-43 is a concern, as well as very strong pathology in brain areas not associated with the disease. Nevertheless, the DPR antibodies will provide a powerful research and diagnostic tool for ALS/FTLD field.

    These two important papers now add RAN translation to two other major hypotheses for the pathological effect of the C9ORF72 mutation, namely, RNA toxicity of the extended repeat and haploinsufficiency of C9ORF72 protein. Interestingly, according to two recent papers (Levine et al., 2013, and Zhang et al.,2013), the C9ORF72 protein may be related to the DENN family of GDP-GTP exchange factors for Rab GTPases involved in membrane trafficking.

    These studies raise new questions:

    1. Are DPRs enough to cause the disease? With such strong cerebellar and hippocampal expression of DPRs, can we consider them as more than a really good marker of C9ORF72 pathology?

    2. Although there is no colocalization between DPRs and TDP-43, C9ORF72 disease is still a TDP-43 proteinopathy. How does the GGGGCC repeat cause TDP-43 aggregation?

    3. The prevailing paradigm in myotonic dystrophy is that the disease is caused by RNA toxicity through aggregation of RNA and sequestration of RNA binding proteins. What are those proteins for the GGGGCC repeat doing in vivo?


    . p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011 Dec;122(6):691-702. PubMed.

    . The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics. 2013 Feb 15;29(4):499-503. Epub 2013 Jan 16 PubMed.

    . Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Front Genet. 2012;3:283. PubMed.

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