Disruption of CSF-1 receptor–mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease
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
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
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Research Article Cell biology Neuroscience

Disruption of CSF-1 receptor–mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease

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

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Figure 3

Early activation of stress and cell death pathways in Csf1r+/– mice and effects of transgenic overexpression of MT1.

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Early activation of stress and cell death pathways in Csf1r+/– mice and ...
(A and B) IPA-based prediction of pathways (A) and biological processes (B) affected in glial and endothelial lineage cells of young Csf1r+/– mice. (C) IPA-based prediction of pathways (upper panel) and biological processes (lower panel) affected in neurons of young Csf1r+/– mice. The small gray spots indicate lack of significance (Z score < 2 and/or P > 0.05). (D) Heatmap showing the expression of cell death–related transcripts. Asterisks mark the position of Mt1, Fth1, and Mt3 gene transcripts encoding proteins involved in metal ion homeostasis. (E) Heatmap showing the expression of EIF2 pathway-related transcripts. AS, astrocytes; OL, oligodendrocytes; μG, microglia, EC, endothelial cells. (F) qRT-PCR validation of selected changes in gene expression in mouse brains. Means ± SEM; 1-tailed Student’s t tests. Each symbol on the chart represents 1 mouse. (G) Expression of cell death and EIF2 pathway genes in patients with CRL. Each circle on the charts represents 1 patient. One-tailed Student’s t tests. (H–L) Proteomic analysis of the effects of Csf1r heterozygosity and Mt1 overexpression in brain macrophages and oligodendrocytes of 3-month-old mice. Data from 5 mice/condition. (H–J) Macrophages. IPA-generated predictions of biological processes (H), pathways (I), and proteins involved in regulation of mitochondrial function and superoxide production (J). (K and L) Oligodendrocytes. (K) IPA-generated predictions of biological processes affected. (L) Changes in the expression of anti- and pro-apoptotic proteins. **Proteins involved in the inhibition (DNAJC3) and activation (EIF2AK4) of the integrated stress response.