C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production and glomerulonephropathy in mice

Abstract

The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation, and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.

Loss of C9orf72 function leads to autoimmunity

“…Transplantation of mutant (−/−) bone marrow cells to wild type (WT) animals caused autoimmunity and premature mortality, whereas transplantation of WT mice bone marrow cells into mutant (−/−) animals improved phenotype (2). This work is in agreement with the work of Atanasio et al (5) who found that C9orf72 null mice developed myeloid expansion, T cell activation and increased plasma cells. C9orf72 null mice had autoantibodies and glomerulopathy, abnormalities reminiscent of SLE.…”

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…Several studies of germline knockout of C9orf72 in mice were published last year that provide insights into how haploinsufficiency of C9orf72 could contribute to neurodegeneration (105)(106)(107). None of the mice in these studies showed neurodegeneration or motor system dysfunction consistent with ALS/FTD phenotypes, suggesting that C9orf72 function is not as critical in mammalian neurons as was observed in lower organisms.…”

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Moreover, increased activated circulating macrophages, abnormal numbers of CD4 T‐cells, antibodies and circulating immune complex have been described in blood of ALS patients, but the results have been inconsistent 70, 71. Interestingly, the development of C9orf72 null mouse models, after identification of a mutated version of this gene in a significant proportion of ALS patients, did not lead to overt motor impairment 72, 73. Instead, an array of peripheral immune organ abnormalities arose, including splenomegaly, lymphadenopathy and eventually an autoimmune‐like phenotype 72, 73.…”

“…Interestingly, the development of C9orf72 null mouse models, after identification of a mutated version of this gene in a significant proportion of ALS patients, did not lead to overt motor impairment 72, 73. Instead, an array of peripheral immune organ abnormalities arose, including splenomegaly, lymphadenopathy and eventually an autoimmune‐like phenotype 72, 73. Nonetheless, macrophages and microglia appeared particularly susceptible, showing lysosomal dysfunction and a proinflammatory state 73.…”