The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology
Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r...
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Elsevier
2024-12-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003450 |
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| author | Jennifer Stables Reiss Pal Barry M. Bradford Dylan Carter-Cusack Isis Taylor Clare Pridans Nemat Khan Trent M. Woodruff Katharine M. Irvine Kim M. Summers Neil A. Mabbott David A. Hume |
| author_facet | Jennifer Stables Reiss Pal Barry M. Bradford Dylan Carter-Cusack Isis Taylor Clare Pridans Nemat Khan Trent M. Woodruff Katharine M. Irvine Kim M. Summers Neil A. Mabbott David A. Hume |
| author_sort | Jennifer Stables |
| collection | DOAJ |
| description | Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation (Csf1rE631K/+) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate human disease pathology. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the Csf1rE631K/+ mutation impact on microglial phenotype, postnatal brain development, age-related changes in gene expression and on prion disease and experimental autoimmune encephalitis (EAE), two pathologies in which microgliosis is a prominent feature. The Csf1rE631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 and 43 weeks of age. There was no selective effect on homeostatic markers e.g. P2ry12, or age-related changes in gene expression in striatum and hippocampus. An epistatic interaction was demonstrated between Csf1rE631K/+ and Cx3cr1EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in hippocampus and striatum. Heterozygous Csf1rE631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, inflammation-associated transcripts in the hippocampus and striatum were suppressed in parallel with microglia-specific transcripts. The results support a dominant inhibitory model of CSF1R-related leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology. |
| format | Article |
| id | doaj-art-50e9fb735e7344ee8935456482dec788 |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-50e9fb735e7344ee8935456482dec7882025-08-20T02:37:45ZengElsevierNeurobiology of Disease1095-953X2024-12-0120310674310.1016/j.nbd.2024.106743The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathologyJennifer Stables0Reiss Pal1Barry M. Bradford2Dylan Carter-Cusack3Isis Taylor4Clare Pridans5Nemat Khan6Trent M. Woodruff7Katharine M. Irvine8Kim M. Summers9Neil A. Mabbott10David A. Hume11Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA 5006, AustraliaThe Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UKThe Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UKMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, AustraliaSimons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4UU, UKSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, AustraliaThe Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UKMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia; Corresponding author.Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation (Csf1rE631K/+) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate human disease pathology. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the Csf1rE631K/+ mutation impact on microglial phenotype, postnatal brain development, age-related changes in gene expression and on prion disease and experimental autoimmune encephalitis (EAE), two pathologies in which microgliosis is a prominent feature. The Csf1rE631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 and 43 weeks of age. There was no selective effect on homeostatic markers e.g. P2ry12, or age-related changes in gene expression in striatum and hippocampus. An epistatic interaction was demonstrated between Csf1rE631K/+ and Cx3cr1EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in hippocampus and striatum. Heterozygous Csf1rE631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, inflammation-associated transcripts in the hippocampus and striatum were suppressed in parallel with microglia-specific transcripts. The results support a dominant inhibitory model of CSF1R-related leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.http://www.sciencedirect.com/science/article/pii/S0969996124003450CSF1RMacrophageKinase-deadLeukoencephalopathy |
| spellingShingle | Jennifer Stables Reiss Pal Barry M. Bradford Dylan Carter-Cusack Isis Taylor Clare Pridans Nemat Khan Trent M. Woodruff Katharine M. Irvine Kim M. Summers Neil A. Mabbott David A. Hume The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology Neurobiology of Disease CSF1R Macrophage Kinase-dead Leukoencephalopathy |
| title | The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology |
| title_full | The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology |
| title_fullStr | The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology |
| title_full_unstemmed | The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology |
| title_short | The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology |
| title_sort | effect of a dominant kinase dead csf1r mutation associated with adult onset leukoencephalopathy on brain development and neuropathology |
| topic | CSF1R Macrophage Kinase-dead Leukoencephalopathy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003450 |
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