. A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration. Brain. 2018 Oct 1;141(10):2908-2924. PubMed.


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  1. This paper from Soloman et al. addresses an important problem in C9ORF72 disease research to date. Dipeptide-repeat (DPR) proteins are observed to be extremely toxic in cell and animal models, and TDP-43 pathology correlates with neuronal loss in postmortem material, however, a link between the two has not been clearly established. The authors suggest a feedback loop in which DPR proteins initiate karyopherin-α2/4 pathology, which is both a cause and a consequence of developing TDP-43 pathology. This model nicely addresses another apparent paradox in the field in which fully penetrant genetic mutations present at birth take many years to manifest in a clinical phenotype, but then produce a rapidly progressive disease; the kinetic shift involved in this change is difficult to explain without some kind of feedback loop.

    The models described in this paper lay out a time course in which DPR pathology precedes TDP-43 pathology. This has been proposed previously, but a direct causal link between the formation of DPRs and TDP-43 pathology has been lacking—indeed, it appears that extensive DPR pathology is present for many years prior to TDP-43 pathology (Vatsavayai et al., 2016) and studies of C9ORF72-ALS have failed to demonstrate significant levels of the most toxic DPRs within dying motor neurons (Davidson et al., 2016). This paper addresses this problem in a Drosophila model in which the development of DPRs is temporally associated with TDP-43 mis-localization. It is difficult to be certain that the observed TDP-43 mis-localization is representative of the changes seen in human disease because TDP-43 mis-localization can be a nonspecific response to cell stress, but the findings are persuasive.

    A great strength of this work is the demonstration of karyopherin-α2/4 pathology in postmortem tissue from both sporadic and C9ORF72+ patients. However, the findings were not always consistent with the proposed model, for example, KPNA4 pathology frequently occurred in the absence of DPR/TDP-43 pathology, suggesting that it can occur independently. The authors suggest that soluble oligomers of DPR/TDP-43 could initiate the KPNA4 pathology without producing observable pathological inclusions and so explain this apparent mismatch.

    The key next step is to determine whether reversing karyopherin-α2/4 pathology can modify the progression of neurodegeneration, perhaps utilizing the mouse model from Laura Ranum’s group which recapitulates many of the key features of the human disease, including the various molecular pathologies (Liu et al., 2016). Success in this experiment would herald a promising therapeutic target, not just for C9ORF72-disease but for all TDP-43 proteinopathy.


    . Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain. 2016 Dec;139(Pt 12):3202-3216. Epub 2016 Oct 22 PubMed.

    . Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins. Neuropathol Appl Neurobiol. 2016 Apr;42(3):242-54. Epub 2015 Dec 7 PubMed.

    . C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. 2016 May 4;90(3):521-34. Epub 2016 Apr 21 PubMed.

    View all comments by Johnathan Cooper-Knock
  2. This is a very interesting study that puts together a potential mechanism linking C9ORF72 dipeptide protein aggregates with TDP-43 pathology. By delineating a sequence of events in the fly model involving karyopherin dysfunction and initial TDP-43 mis-localization, they set the stage nicely for testing whether this is a universal pathway seen in other models and human tissues. Likewise, they open the exciting possibility that one can therapeutically intervene between the appearance of DPRs (an early event that does not correlate with neurodegeneration) and TDP-43 aggregation (a late event that does correlate with neurodegeneration). A remaining question will be how to correlate this sequence of molecular events which occurs relatively rapidly in flies with the process in humans, where DPRs occur years or decades before TDP-43 pathology and neurodegeneration.

    View all comments by Robert Baloh
  3. This new paper by Frank Hirth and colleagues provides clear evidence that poly-GR itself can directly lead to altered TDP-43 localization in flies. It was interesting that poly-GA led to a distinct change in TDP-43 localization, which appeared due to the sequestration of TDP-43 with cytoplasmic poly-GA aggregates. Poly-GR, in contrast, led to a more diffuse mis-localisation of TDP-43 that was not associated with aggregates of poly-GR. This implies the different DPRs induce TDP-43 alterations via different mechanisms. Consistent with previous results, factors involved in nucleocytoplasmic transport were also mis-localized.

    Based on the timing of these events, the authors suggest that TDP-43 mis-localization is the trigger for altered nucleocytoplasmic transport. This is consistent with the idea that DPRs are the initiators and TDP-43 the executioner, akin to Aβ and tau in Alzheimer’s disease (Edbauer and Haass, 2016). This sequence of events is well-supported in the literature, but there is still work to do to better understand the link between DPRs and TDP-43 and why we see very little overlap between TDP-43 and DPR inclusions in patient brains.


    . An amyloid-like cascade hypothesis for C9orf72 ALS/FTD. Curr Opin Neurobiol. 2016 Feb;36:99-106. Epub 2015 Nov 8 PubMed.

    View all comments by Adrian Isaacs
  4. I enjoyed reading this publication. I would be interested to know if there would be a way to restore KPNA2/4 function and/or localization and provide a phenotypic rescue downstream of DPR and TDP-43 accumulation in the cytoplasm. With regard to the absence of nuclear pore complex and nucleocytoplasmic transport phenotypes in their publication, I would be curious if they would see emergence of these if they had examined their G4C2-38 flies, which express both G4C2 RNA and GR DPR. It may be that these phenotypes are dependent on both RNA and DPR production simultaneously.

    View all comments by Brian Freibaum
  5. Several years after the discovery of the C9ORF72 repeat expansion as a major genetic cause of ALS/FTD, there is still a lot of controversy over its disease mechanisms, and the role that the formation of RNA foci and the accumulation of DPR proteins play in the disease process. A related question of importance in the field is how C9ORF72 repeat expansions can trigger TDP-43 pathology, the near universal neuropathological hallmark of ALS. There are now several conflicting studies that attribute TDP-43 pathology to either RNA repeat or DPR toxicity. While this new work is interesting, and provides support for an important role of DPRs in this process, it is unlikely to end the controversy. This paper also confirms previous studies on relative DPR toxicity in Drosophila, with arginine-rich peptides being more toxic than other DPR species. It would be interesting to see how the combination of different DPRs that are present together in human patients affect the phenotype of disease models.

    View all comments by Wilfried Rossoll

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  1. Dipeptide Repeat Proteins Trigger TDP-43 Pathology, Faulty Nuclear Import