Citations 1
Disruption of CSF-1 receptor–mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease
Chiţu, Violeta , Alvarenga, Julia, Chen, Wenna, Reynolds, David, Liu, Yang , Sun, Daqian, Sandell, A. , Karrenbauer, Virginjia Danylaite, Uvdal, P. , Silva, Iran An Da, Johansson, Ulf, Vignesh, Kavitha Subramanian , Wszolek, Zbigniew K., Dickson, Dennis W., Aguilan, Jennifer T. , Sidoli, Simone, Zheng, Deyou , Stanley, E. Richard, Karrenbauer, Virginija Danylaité , Danylaité Karrenbauer, Virginija , Sandt, Christophe , Klementieva, Oxana l. , Johansson, Ulf, Dickson, Dennis W. , Stanley, E. Richard
Journal of Clinical Investigation | February 26, 2026 | Volume: 136 | Issue: 9 | Pages: No page available
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.