. Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD. EMBO J. 2020 Apr 15;39(8):e102811. Epub 2020 Mar 16 PubMed.


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  1. Much study on C9ORF72-ALS has centered on toxicity mediated by dipeptide repeat proteins translated from the GGGGCC-repeat expansion. Despite this work, a fundamental question has remained over the relative absence of dipeptide-repeat protein pathology in postmortem tissue and the lack of correlation between dipeptide-repeat protein pathology and the presence of TDP-43 pathology. Cytoplasmic TDP-43 proteinaceous inclusions remain the only molecular marker that predicts neuronal loss. Moreover, clinically and pathologically, neurotoxicity spreads between contiguous areas of the nervous system and this, too, is unexplained.

    This paper from the Edbauer lab offers a proposal—that poly-GA dipeptide-repeat proteins can induce TDP-43 pathology via inhibition of proteasome activity; and that poly-GA proteins can transmit disease between adjacent cells such that a single cell containing a poly-GA protein aggregate may induce toxicity in all neighboring cells. The authors suggest that the lack of correlation between observed postmortem poly-GA and TDP-43 pathology is a result of a third independent variable, that is, baseline proteasome activity. It follows that in areas of the brain such as the cerebellum there is high baseline proteasome activity, so despite plentiful poly-GA pathology the proteasome is not successfully inhibited and TDP-43 pathology is rare. Alternatively, in spinal motor neurons, where baseline proteasome activity is low, a relatively low abundance of poly-GA pathology is sufficient to induce TDP-43 pathology and therefore neurotoxicity. 

    The authors have provided detailed mechanistic insight into this process. This included identification of a key K95-TDP-43 residue that is ubiquitinated in the presence of poly-GA mediated proteasome inhibition, resulting in impaired NLS function and thus cytoplasmic mislocalization of TDP-43.

    This is a well-thought-out hypothesis. Proof will require an in vivo demonstration that inhibition of poly-GA transmission can slow the development of TDP-43 pathology and clinical progression. Arguably, a suitable animal model for such an experiment does not exist currently. 

    Certain other questions remain, as well: poly-GA is absent in the majority of ALS patients who do not have a C9ORF72-expansion, but the clinical progression of C9ORF72-ALS is not significantly different to non-C9ORF72-ALS. How does this mechanism fit into a non-C9ORF72-ALS model? Finally, poly-GA pathology has been demonstrated years in advance of disease onset and the development of TDP-43 pathology (Vatsavayai et al., 2016). What explains the delay in development of TDP-43 mislocalization which preceeds disease onset?


    . 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.

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  2. Accumulating evidence suggests that the transmission of glycine-alanine (GA) dipeptide repeats (DPRs) could be a relevant phenomenon in C9ORF72 ALS/FTD. This event has now been shown in four independent cell culture studies (Chang et al., 2016; Flores et al., 2016; Westergard et al., 2016; Zhou et al., 2017) and we also recently reported it in vivo using different neuronal populations of the fly brain (Morón-Oset et al., 2019). However, what exactly this transmission entails for the disease remains unclear.

    In this elegant study, the Edbauer lab provides compelling evidence that transmission of GA175-eGFP between primary rat neurons or Hela cells causes accumulation of cytoplasmatic TDP-43, which is a classical feature of ALS and FTD (Neumann et al., 2006). In agreement with a recent paper showing the close association between GA and the proteasome in cell culture (Guo et al., 2018), this novel study also shows that GA-mediated proteasome inhibition in both donor and recipient cells is key to cause cytoplasmatic retention of TDP-43, which can be rescued by activating the proteasome with the drug rolipram. These are very interesting findings and pose the question  whether this is a specific event for TDP-43 or whether GA would have a similar effect for other proteasome substrates. In addition, while it is still somewhat unclear whether GA prevents the degradation of TDP-43 during its physiological turnover or whether it somehow enhances its nuclear export, the retention of a few ubiquitinated TDP-43 molecules in the cytoplasm could suffice to create the first seeds that would then go on to cause the vast accumulation of TDP-43 aggregates in the cytoplasm and lack of nuclear TDP-43 typically observed in ALS and FTD patients at autopsy. Hence the great relevance of this study. It will be interesting to test whether this cascade of events can also occur under in vivo conditions, as well as whether it can lead to neuronal dysfunction and subsequent death.


    . The Glycine-Alanine Dipeptide Repeat from C9orf72 Hexanucleotide Expansions Forms Toxic Amyloids Possessing Cell-to-Cell Transmission Properties. J Biol Chem. 2016 Mar 4;291(10):4903-11. Epub 2016 Jan 14 PubMed.

    . Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity. PLoS One. 2016;11(10):e0165084. Epub 2016 Oct 24 PubMed.

    . In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment. Cell. 2018 Feb 8;172(4):696-705.e12. Epub 2018 Feb 1 PubMed.

    . Glycine-alanine dipeptide repeats spread rapidly in a repeat length- and age-dependent manner in the fly brain. Acta Neuropathol Commun. 2019 Dec 16;7(1):209. PubMed.

    . Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. PubMed.

    . Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD. Cell Rep. 2016 Oct 11;17(3):645-652. PubMed.

    . Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins. EMBO Mol Med. 2017 May;9(5):687-702. PubMed.

    View all comments by Javier Morón-Oset

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  1. Traveling C9ORF72 Dipepides Jam Proteasomes in Neighboring Neurons