. C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo. Nat Neurosci. 2019 Jun;22(6):851-862. Epub 2019 May 13 PubMed.

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  1. This paper nicely shows that expression of a poly(GR) in all the layers of the cortex under the control of a CamKII promotor can induce an ALS/FTD-related phenotype. A major advantage of this study is that the poly(GR) is expressed at a relatively low level and that phenotypes induced by huge overexpression of the transgene are avoided.

    Another very interesting characteristic of the system used in this study is that the expression of poly(GR) can be reduced by feeding the mice with doxycycline. Interestingly, behavioral and even the cellular phenotypes can be significantly reversed when the expression of poly-GR is lowered. This is fascinating and has far-reaching consequences. It strongly indicates that therapeutic strategies lowering the expression of toxic dipeptide-repeat proteins can reverse disease phenotypes, even after disease onset. This reversal of the phenotype can be considered as a very interesting new insight, in addition to the systematic characterization of the underlying disease mechanism, which is related to mitochondrial dysfunction.

  2. This paper describes an interesting new poly(GR)-expressing mouse model. We will need a range of different models to ultimately understand the role of each DPR and their contribution to C9ORF72-repeat pathology, so this is a welcome addition.

    The most striking finding is that neuronal loss and synaptic dysfunction are identified even though GR is not detectable by immunostaining until six to eight months of age (although it can be detected earlier with ELISA). This suggests relatively low levels of likely soluble GR are sufficient to induce neurodegeneration.

    The paper also links poly(GR) to an early defect in mitochondrial function, which could explain the later development of DNA damage. Many pathways have been implicated in C9ORF72-repeat-induced neurodegeneration, and mitochondrial dysfunction should now be added as a new avenue for further investigation. Consistent with the previously reported AAV poly(GR) mouse model, no TDP-43 pathology was observed, and so the link between DPRs and TDP-43 is still an outstanding question.

  3. This is a very nice addition to the building literature on mechanisms of toxicity from DPR expression in animal models. It brings to light a surprisingly specific mechanism, whereby poly(GR) alters mitochondrial ATP5A1, further linking mitochondrial dynamics and dysfunction to neurodegeneration and providing a potential therapeutic avenue.

    Challenges going forward for the field include interpreting this mechanism of toxicity in the context of the numerous other toxicities of the different DPRs, and determining whether some are more important than others, and where and when they are happening in human disease. 

    Regardless, it provides further support for the idea that diminishing gain-of-function products of the C9ORF72 repeat could have a therapeutic effect, and many of these strategies are in preclinical or clinical phase testing.

  4. This work provides an additional mouse model and research tool for the C9 ALS/FTD community. Because C9 ALS/FTD disease is a complex disease, with the expression of two mutant transcripts (sense and antisense) and six dipeptide repeat-containing proteins, which are produced by repeat-associated non-AUG (RAN) translation, this polyGR-expressing mouse model is a simplified model for studying the potential contribution of polyGR to disease pathology.

    The paper provides a compelling data set showing that moderate expression of polyGR causes mitochondrial dysfunction that is linked to reductions in Atp5a1. In the future, it will be interesting to test if strategies described to reverse GR toxicity improve phenotypes in mouse models that express the repeat expansion and produce the multiple types of RAN proteins found in patients. It will also be of interest to test if Atp5a1 levels are reduced in these G4C2 mouse models and also in C9 patient tissues.

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  1. C9ORF72 Toxicity Tied to Mitochondria, Transcriptional Machinery