Disruption of CSF-1 receptor-mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease
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
- Kavitha Subramanian Vignesh (ORCID: https://orcid.org/0000-0002-2943-2988)
- Jennifer T. Aguilan (ORCID: https://orcid.org/0000-0002-0221-354X)
- Iran An Da Silva
- Christophe Sandt (ORCID: https://orcid.org/0000-0002-6432-2004)
- Oxana Klementieva (ORCID: https://orcid.org/0000-0003-1782-050X)
- P. Uvdal (ORCID: https://orcid.org/0000-0002-2121-3377)
- Deyou Zheng
- A. Sandell (ORCID: https://orcid.org/0000-0002-6120-7502)
- Violeta Chiţu (ORCID: https://orcid.org/0000-0001-6641-1564)
- Daqian Sun
- Simone Sidoli
- Virginjia Danylaite Karrenbauer
- Zbigniew K. Wszolek
- E. Richard Stanley
- Wenna Chen
- Dennis W. Dickson
- Ulf Johansson
- Julia Alvarenga
- Yang Liu
- David Reynolds
Institutions
- Uppsala University (SE)
- Albert Einstein College of Medicine (US)
- Lund University (SE)
- Synchrotron soleil (FR)
- Jacksonville College (US)
- Karolinska Institutet (SE)
- MAX IV Laboratory (SE)
- Mayo Clinic in Florida (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-02-26
- DOI
- https://doi.org/10.1172/jci200121
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Eli Lilly and Company
- EU Joint Programme – Neurodegenerative Disease Research
- VINNOVA
- Svenska Forskningsrådet Formas
- Carl Tryggers Stiftelse för Vetenskaplig Forskning
- Vetenskapsrådet
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke