PUBLICATION
Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy
- Authors
- Berdowski, W.M., van der Linde, H.C., Breur, M., Oosterhof, N., Beerepoot, S., Sanderson, L., Wijnands, L.I., de Jong, P., Tsai-Meu-Chong, E., de Valk, W., de Witte, M., van IJcken, W.F.J., Demmers, J., van der Knaap, M.S., Bugiani, M., Wolf, N.I., van Ham, T.J.
- ID
- ZDB-PUB-220622-26
- Date
- 2022
- Source
- Acta Neuropathologica 144(2): 211-239 (Journal)
- Registered Authors
- van der Linde, Herma, van Ham, Tjakko
- Keywords
- ALSP, Astrocytes, CSF1R, Leukodystrophy, Microglia, Zebrafish models
- MeSH Terms
-
- Adult
- Animals
- Astrocytes/pathology
- Demyelinating Diseases*/pathology
- Humans
- Leukoencephalopathies*/genetics
- Leukoencephalopathies*/pathology
- Lysosomal Storage Diseases*/metabolism
- Microglia/pathology
- Neurodegenerative Diseases*/pathology
- Phenotype
- Receptor Protein-Tyrosine Kinases/genetics
- Receptor Protein-Tyrosine Kinases/metabolism*
- Zebrafish
- Zebrafish Proteins/metabolism*
- PubMed
- 35713703 Full text @ Acta Neuropathol.
Citation
Berdowski, W.M., van der Linde, H.C., Breur, M., Oosterhof, N., Beerepoot, S., Sanderson, L., Wijnands, L.I., de Jong, P., Tsai-Meu-Chong, E., de Valk, W., de Witte, M., van IJcken, W.F.J., Demmers, J., van der Knaap, M.S., Bugiani, M., Wolf, N.I., van Ham, T.J. (2022) Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy. Acta Neuropathologica. 144(2):211-239.
Abstract
Tissue-resident macrophages of the brain, including microglia, are implicated in the pathogenesis of various CNS disorders and are possible therapeutic targets by their chemical depletion or replenishment by hematopoietic stem cell therapy. Nevertheless, a comprehensive understanding of microglial function and the consequences of microglial depletion in the human brain is lacking. In human disease, heterozygous variants in CSF1R, encoding the Colony-stimulating factor 1 receptor, can lead to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) possibly caused by microglial depletion. Here, we investigate the effects of ALSP-causing CSF1R variants on microglia and explore the consequences of microglial depletion in the brain. In intermediate- and late-stage ALSP post-mortem brain, we establish that there is an overall loss of homeostatic microglia and that this is predominantly seen in the white matter. By introducing ALSP-causing missense variants into the zebrafish genomic csf1ra locus, we show that these variants act dominant negatively on the number of microglia in vertebrate brain development. Transcriptomics and proteomics on relatively spared ALSP brain tissue validated a downregulation of microglia-associated genes and revealed elevated astrocytic proteins, possibly suggesting involvement of astrocytes in early pathogenesis. Indeed, neuropathological analysis and in vivo imaging of csf1r zebrafish models showed an astrocytic phenotype associated with enhanced, possibly compensatory, endocytosis. Together, our findings indicate that microglial depletion in zebrafish and human disease, likely as a consequence of dominant-acting pathogenic CSF1R variants, correlates with altered astrocytes. These findings underscore the unique opportunity CSF1R variants provide to gain insight into the roles of microglia in the human brain, and the need to further investigate how microglia, astrocytes, and their interactions contribute to white matter homeostasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping