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

Chitu, Violeta ; Alvarenga, Julia ; Chen, Wenna ; Reynolds, David ; Liu, Yang ; Sun, Daqian ; Sandell, Anders ; Danylaite Karrenbauer, Virginjia ; Uvdal, Per LU and da Silva, Iran A. N. LU orcid , et al. (2026) In JCI Insight
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
JCI Insight
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:41746753
  • scopus:105037865713
ISSN
2379-3708
DOI
10.1172/JCI200121
language
English
LU publication?
yes
id
35a9344b-23e2-497f-a4ed-bc9bc9d5bd93
date added to LUP
2026-03-02 20:45:59
date last changed
2026-05-21 04:01:13
@article{35a9344b-23e2-497f-a4ed-bc9bc9d5bd93,
  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.}},
  author       = {{Chitu, Violeta and Alvarenga, Julia and Chen, Wenna and Reynolds, David and Liu, Yang and Sun, Daqian and Sandell, Anders and Danylaite Karrenbauer, Virginjia and Uvdal, Per and da Silva, Iran A. N. and Sandt, Christophe and KLEMENTIEVA, Oxana and Johansson, Ulf and Subramanian Vignesh, Kavita and Wszolek, Zbigniew K. and Dickson, Dennis W and Aguilan, Jennifer and Sidoli, Simone and Zheng, Deyou and Stanley, E. Richard}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Disruption of CSF-1 receptor-mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease}},
  url          = {{http://dx.doi.org/10.1172/JCI200121}},
  doi          = {{10.1172/JCI200121}},
  year         = {{2026}},
}