(Fig. 1 a), which is in line with a recent study by Atanasio et al.[1] who report, but do not specify, decreased survival rates. In line with our previous observations [3], full C9orf72 ablation results in a 5.9% decrease in body weight (P= 0.0056), without affecting motor function (accelerating rotarod and grip strength test) or inducing pathological hallmarks of ALS (see also [1, 2]), such as motor neuron degeneration, gliosis, enhanced ubiquitination and TDP-43 mislocalization. However, post-mortem analysis of full C9orf72 knockout mice (n= 5; 11–15 months of age) revealed enlarged lymph nodes (LNs)(n= 4 mice) and splenomegaly (n= 5)(Fig. 1 b). Detailed histological evaluation detected massive infiltration of histiocytes/macrophages and lymphocytes in multiple organs, including LNs, spleen, bone marrow, liver, kidney and lung (Fig. 1 c–k). In addition to these immunological phenotypes, which are in part also reported by Atanasio et al.[1] and O’Rourke et al.[2], we detect evidence of neoplastic events. LNs of several animals (n= 4) contained infiltrates of B220/CD45R-positive B-lymphocytes that disrupted tissue architecture and were accompanied by increased expression of the proliferation marker Ki67, suggesting the development of B-cell lymphomas (Fig. 1 c–e). Furthermore, disrupted tissue architecture and homogeneous populations of F4/80-positive macrophages expressing Ki67 were present in LNs (n= 3), spleen (n= 3), liver (n= 1) and lung (n= 1). Moreover, infiltrating cells in the liver and lung accumulated in intravascular spaces (Fig. 1 f–k), suggesting the occurrence of metastatic histiocytic sarcomas. These results indicate that the defects in immune cell function recently reported in C9orf72 knockout mice (eg changes in endosome/lysosomal trafficking, cytokine production)[1, 2] may ultimately lead to neoplastic events in multiple organs. These findings have important implications as they indicate that strategies aimed at lowering systemic C9ORF72 levels

Non-coding hexanucleotide (GGGGCC) repeat expansions in C9ORF72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD; C9ALS/FTD). Decreased C9orf72 protein levels in C9ALS/FTD patients [4] support the idea that C9ORF72 haploinsufficiency may contribute to disease pathogenesis. To test this hypothesis, we previously generated and analyzed neural-specific C9orf72 knockout mice. Our results showed that neural-specific ablation of C9orf72 (3110043O21Rik) in mice does not cause motor neuron degeneration or changes in motor function [3]. We therefore concluded that loss of C9ORF72 on its own is unlikely to cause ALS and that reducing C9ORF72 levels may comprise a promising strategy to treat C9-ALS patients. This therapeutic potential led us, and others [1, 2], to subsequently analyze knockout mice lacking C9orf72 in all tissues. Importantly, in contrast to our previous report, we find that full ablation of C9orf72 induces reduced survival