. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron. 2014 Dec 17;84(6):1213-25. PubMed.


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  1. To use a sports analogy it's now 3:3—the glycine-alanine camp (May et al., 2014; Zhang YJ et al., 2014; Yamakawa M et al., 2014) and the arginine-rich camp (Kwon I et al., 2014; Mizielinska S et al., 2014; Wen X et al., 2014) are tied. I find the cell type specific toxicity and the interaction of dipeptide repeat (DPR) and RNA toxicity the most interesting results in this, the latest DPR toxicity paper from the Trotti lab. Moreover, it's nice that somebody finally published that C9ORF72 knockdown is not overtly neurotoxic, which argues against a major role for C9ORF72 loss of function in ALS/FTD.

    I still favor the role of glycine-alanine toxicity for the pathogenesis, although recombinant proline-arginine and glycine-arginine clearly can induce toxicity in various systems (including some of our experiments). My main concern with PR/GR toxicity is the nucleolar aggregation pattern of recombinant PR and GR proteins in vitro, which is in contrast to the predominant cytoplasmic aggregation of PR and GR seen in patient brains. At least with our antibodies, the less common nuclear aggregates don't seem to co-localize with nucleoli. Also, unlike the DPR inclusions in patients, the aggregates of recombinant PR/GR are p62 negative. Since recombinant GA expressed in cell culture looks very similar to GA found in patient tissue, we have been focusing our analysis on GA toxicity.

    I believe that when two camps are arguing in science, the truth usually lies in between. Mouse models and more detailed neuropathological analysis will be important for settling this issue. If nucleolar PR/GR is indeed the main culprit, I expect that future studies will find a better correlation between this regional neurodegeneration and this specific pathology rather than for GA aggregates. On the other hand, if cells with nucleolar PR/GR aggregates die too quickly to be found in postmortem tissue, it will be hard to show their clinical relevance other than by removing them therapeutically.

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