. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med. 2016 Jul 13;8(347):347ra93. PubMed.


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  1. This detailed study from Burberry et al. describes a new mouse model with C9ORF72 loss-of-function. The study largely confirms the findings of earlier studies (O’Rourke et al., 2016Atanasio et al., 2016)—loss of the murine C9ORF72 ortholog results in splenomegaly and proliferation of immune cells without a notable neuromuscular phenotype. Like the Atanasio et al. study, Burberry and colleagues identified an autoimmune phenotype. Interestingly they showed that transplantation of wild-type bone marrow was sufficient to ameliorate the phenotype of C9ORF72-null mice.

    Whilst this has clear implications for proposed antisense oligonucleotide therapy aimed at reducing expression of mutant C9ORF72, the authors also draw attention to wider evidence for immune dysfunction in amyotrophic lateral sclerosis (ALS) and in particular, the striking similarity between the phenotype of these mice and TBK1-mull mice (Marchlik et al., 2010). The suggestion is that C9ORF72 loss-of-function may be important to ALS pathogenesis even if it is not the primary cause of neurotoxicity.

    Indeed the role of neuroinflammation in neurodegenerative disease is a growing area; an attractive hypothesis is that patients with heterozygous mutations in C9ORF72 experience immune dysfunction due to haploinsufficiency, which interacts synergistically with a gain of function of the GGGGCC-repeat expansion, resulting in neuronal-specific toxicity. We await studies describing C9ORF72-null mice engineered to express the expanded human gene. However, a recent study from the lab of Laura Ranum suggested that expression of the expansion in the context of the full-length human C9ORF72 gene is sufficient to recapitulate a motor neuron disease phenotype (Liu et al., 2016). Given the variability in the human disease, perhaps it is not surprising that a picture of multiple causal factors and modifiers is being uncovered. 


    . C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016 Mar 18;351(6279):1324-9. PubMed.

    . C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep. 2016 Mar 16;6:23204. PubMed.

    . Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality. J Leukoc Biol. 2010 Dec;88(6):1171-80. Epub 2010 Jul 22 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.

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  1. Paper Alert: Autoimmunity in Another C9ORF72-Deficient Mouse Strain