Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72gene are the major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although the expansion decreases C9orf72 expression, most research has focused on the toxic RNA and protein products it creates in neurons.

Researchers found that C9orf72 unexpectedly plays a key role in innate immune cells. They found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. 

C9orf72 expression was highest in myeloid cells, and the loss ofC9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue.

Loss of C9orf72 in mice led to macrophage and microglial dysfunction and age-related neuroinflammation.

Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration inC9orf72 expansion carriers.

http://science.sciencemag.org/content/351/6279/1324