The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology.

Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation (Csf1r) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate human disease pathology. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the Csf1r mutation impact on microglial phenotype, postnatal brain development, age-related changes in gene expression and on prion disease and experimental autoimmune encephalitis (EAE), two pathologies in which microgliosis is a prominent feature. The Csf1r mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 and 43 weeks of age. There was no selective effect on homeostatic markers e.g. P2ry12, or age-related changes in gene expression in striatum and hippocampus. An epistatic interaction was demonstrated between Csf1r and Cx3cr1 genotypes leading to dysregulated microglial and neuronal gene expression in hippocampus and striatum. Heterozygous Csf1r mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, inflammation-associated transcripts in the hippocampus and striatum were suppressed in parallel with microglia-specific transcripts. The results support a dominant inhibitory model of CSF1R-related leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.