Abstract
Dominant-inactivating mutations in the colony stimulating factor-1 receptor (CSF1R) cause CSF-1R–related leukoencephalopathy (CRL), an adult-onset neurodegenerative disease that is modeled in the Csf1r+/– mouse. CRL is caused by microglial dysfunction. However, the primary microglial deficit is unknown. To address this question, we employed single-nucleus RNA sequencing of brains from young Csf1r+/– mice without pathological or behavioral alterations. Reduction of CSF-1R signaling caused metal ion accumulation in brain macrophages, with concomitant activation of cell death and stress response pathways in oligodendrocytes and neuronal subpopulations. Reduction of metallothionein 1 (Mt1) and 3 (Mt3) gene expression was a common feature in glial and neuronal cells of Csf1r+/– mice. Overexpression of Mt1 restored metal ion homeostasis, normalized ROS production in microglia, and prevented the development of behavioral deficits, while Mt3 deletion had disease-enhancing effects. These findings demonstrate CSF-1R regulation of metal ion homeostasis via metallothioneins in the brain.
Authors
Violeta Chițu, Julia Alvarenga, Wenna Chen, David Reynolds, Yang Liu, Daqian Sun, Anders Sandell, Virginjia Danylaité-Karrenbauer, Per Uvdal, Iran A.N da Silva, Christophe Sandt, Oxana Klementieva, Ulf Johansson, Kavitha Subramanian Vignesh, Zbigniew K. Wszolek, Dennis W. Dickson, Jennifer T. Aguilian, Simone Sidoli, Deyou Zheng, E. Richard Stanley
Figure 6
Overexpression of
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ISSN: 0021-9738 (print), 1558-8238 (online)