Abstract
CSF-1R haploinsufficiency causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Previous studies in the Csf1r+/- mouse model of ALSP hypothesized a central role ofelevated cerebral Csf2 expression. Here, we showthat monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r+/- mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination. We also show elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients, demonstrating that the mechanisms identified in the mouse model are functional in humans. Our data provide insights into the mechanisms underlying ALSP. Because increased CSF2 levels and decreased microglial Csf1r expression have also been reported in Alzheimer's disease and multiple sclerosis, we suggest that the unbalanced CSF-1R/CSF-2 signaling we describe in the present study may contribute to the pathogenesis of other neurodegenerative conditions.
Highlights
The colony-stimulating factor-1 receptor (CSF-1R) is regulated by two cognate ligands, CSF-1 and interleukin-34; is expressed on microglia; and is required for their development and maintenance
Monoallelic Targeting of Csf2 Prevents White Matter Microgliosis in Young Csf1r+/À Mice Because colony-stimulating factor-2 (CSF-2) is a microglial mitogen (Lee et al, 1994), and Csf1r+/À mice exhibit early-onset microgliosis (Chitu et al, 2015), we initially examined the effect of genetic targeting of Csf2 on Iba-1+ microglia density in young Csf1r+/À mice
Csf2 homozygous deletion showed no additional effects over Csf2 heterozygosity
Summary
The colony-stimulating factor-1 receptor (CSF-1R) is regulated by two cognate ligands, CSF-1 and interleukin-34; is expressed on microglia; and is required for their development and maintenance (reviewed in Chitu et al, 2016). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), known as hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia or pigmented orthochromatic leukodystrophy, is an autosomaldominant, neurodegenerative disorder caused by mutations of the CSF1R gene (reviewed in Konno et al, 2018). The discovery of an ALSP patient with a CSF1R frameshift mutation that abolished CSF-1R protein expression proved that CSF1R haploinsufficiency is sufficient to cause ALSP (Konno et al, 2014)
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