Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease

Abstract

C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. Here, we show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant bone marrow into wildtype recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wildtype marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity.

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

“…However, zebrafish models show reduced axon length in motoneurons and reduced locomotion after antisense morpholino-mediated reduction of C9ORF72 levels 5 . In contrast to the results in C. elegans and zebrafish, studies in mouse have so far not revealed conclusive results for C9ORF72 loss of function as a possible cause of FTLD/ALS [13][14][15][16] . Administering antisense oligonucleotides (ASOs) targeting mouse C9ORF72 by stereotactic intracerebroventricular (ICV) injection reduced C9ORF72 mRNA levels to 30-40% of control levels in the spinal cord and brain 17 .…”

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…The studies of C9orf72-null mice showed variability in the degree of autoantibody production and autoimmune-mediated tissue injury, indicating an environmental influence from different housing conditions that contributed to the development of autoimmunity. Interestingly, even heterozygous C9orf72 (C9orf72 +/-) animals showed a limited repertoire of autoantibodies with increased risk of early mortality (107), and bone marrow-derived macrophages from C9orf72 +/-mice also showed altered cytokine responses to a variety of immune stimuli (106). Together these studies support (a) that complete loss of…”

“…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.…”

RNA versus protein toxicity in C9orf72 ALS/FTLD

“…Homozygous knockout of C9orf72 causes a variable (lupuslike) immune phenotype due to strong expression of C9orf72 in the myeloid lineage, but the mice show no overt neurodegeneration [1,20]. However, C9orf72 haploinsufficiency sensitizes patient-derived motoneurons to DPR toxicity and other stressors, suggesting it may contribute to neurodegeneration in C9orf72 ALS/FTD [28].…”