. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. 2015 Jun 5;348(6239):1151-4. Epub 2015 May 14 PubMed.


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  1. This is an exciting and potentially very important new model system for C9 forms of ALS and FTLD. The paper underscores the utility of somatic cell gene transfer with AAV vectors for disease modeling. The vector approach is rapid and therefore expedites hypothesis testing.

    View all comments by Ronald Klein
  2. This paper by Chew et al. describes a mouse model that recapitulates the neuropathological and clinical phenotypes of the G4C2 hexanucleotide repeat expansion in C9ORF72, the major genetic cause of FTD and ALS. The mice were generated by intracerebroventricular AAV-injection of two or 66 G4C2 repeats at postnatal day zero. The neuropathological and behavioral phenotypes were examined at six months post-injection.

    Similarly to the C9FTD/ALS patients, the (G4C2)66 mice showed the presence of nuclear RNA foci and ubiquitin-positive C9RAN inclusions, as well as expression of poly(GP) dipeptides. The mice also developed phospho-TDP43-containing inclusions, but these, even when they resided in the same cells as poly(GA) inclusions, did not contain poly(GA). These findings are in accordance with previous data from human patients, which have indicated that the dipeptide repeat (DPR)-containing inclusions are separate from those harboring phospho-TDP-43 (Mori et al., 2013). Here, Chew et al. also present an intriguing idea that the extended G4C2 repeats might function as initiators of TDP-43 pathology. On the other hand, because TDP-43 inclusions are present also in ALS or FTD patients not carrying the G4C2 repeat expansion, the extended repeats may not represent the sole trigger of the TDP-43 pathology. Nevertheless, in G4C2 expansion cases, DPRs might function as initiators or modulators and thus result in the development of enhanced TDP-43 pathology. Characterization of the potential underlying mechanism(s) and further testing of this interesting idea by using other approaches, for example, antisense oligonucleotides to block the generation of the extended repeats in these mice, will provide more information on this plausible relationship.

    In addition to the typical neuropathological changes, behavioral changes were detected in (G4C2)66 mice compared to (G4C2)2 mice. (G4C2)66 mice exhibited hyperactivity and anxiety-like and asocial behaviors, which are typical symptoms in patients with the C9ORF72-associated behavioral variant FTD. Also, motor skill deficits were noticed in (G4C2)66 mice, but a decrease in body weight was detected only in females. Thus, it seems that the (G4C2)66 mice exhibit more of the clinical features of behavioral-variant FTD than of ALS.

    Taken together, the (G4C2)66 mice represent the first mammalian model widely recapitulating both neuropathological and behavioral alterations associated with the C9ORF72 G4C2-repeat expansion in human FTD and ALS patients. The model provides excellent possibilities for further characterizations and understanding of the mechanisms of FTD/ALS pathogenesis as well as for testing emerging therapeutic approaches. 


    . The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013 Mar 15;339(6125):1335-8. Epub 2013 Feb 7 PubMed.

    View all comments by Annakaisa Haapasalo

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