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CSF-1R regulates metal ion homeostasis in the brain – implications for neurodegenerative disease

ABSTRACT: Dominant inactivating mutations in the colony stimulating factor-1 receptor (CSF1R) cause an adult-onset neurodegenerative disease associated with white matter loss and axonal degeneration designated CSF-1R related leukoencephalopathy (CRL), that is modeled in the Csf1r+/- mouse. CRL is caused by microglial dysfunction. However, the primary microglial deficit, caused by insufficient CSF-1R signaling, 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 defects in mitochondrial function and metal ion homeostasis 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 deletiion had disease-enhancing effects. These findings identify a novel role of the CSF-1R in the regulation of metal ion homeostasis in the brain.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD067561 | Pride | 2026-02-18

REPOSITORIES: Pride

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			Action	DRS
	20230714_Jenny_Violeta_Mt1_HTg1_OL_31.raw	Raw
	20230714_Jenny_Violeta_Mt1_HTg1_uG_11.raw	Raw
	20230714_Jenny_Violeta_Mt1_HTg2_OL_32.raw	Raw
	20230714_Jenny_Violeta_Mt1_HTg2_uG_12.raw	Raw
	20230714_Jenny_Violeta_Mt1_HTg3_OL_33.raw	Raw

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CSF-1R regulates metal ion homeostasis in the brain – implications for neurodegenerative disease

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