Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy

Woutje M. Berdowski, Herma C. van der Linde, Marjolein Breur, Nynke Oosterhof, Shanice Beerepoot, Leslie Sanderson, Lieve I. Wijnands, Patrick de Jong, Elisa Tsai-Meu-Chong, Walter de Valk, Moniek de Witte, Wilfred F.J. van IJcken, Jeroen Demmers, Marjo S. van der Knaap, Marianna Bugiani, Nicole I. Wolf, Tjakko J. van Ham*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)211-239
Number of pages29
JournalActa Neuropathologica
Issue number2
Publication statusPublished - Aug 2022

Bibliographical note

Funding Information:
We thank Inge Huitinga (Netherlands Institute for Neuroscience) and the Netherlands Brain Bank for providing pHrodo-labeled myelin and post-mortem brain tissue of ALSP patients and controls, James M Powers (University of Rochester Medical Center), providing the 4 POLD patients, Harro Seelaar and Shami Melhem (Erasmus MC) for providing post-mortem brain tissue of AD and FTD patients, and Saif Haify for helping with immunohistochemical staining of patient tissue. Funding was provided by two Erasmus University Rotterdam fellowships (TVH). MKN, MB, SB and NIW are members of the European reference network for rare neurological disorders (ERN-RND), project ID 739510.

Publisher Copyright:
© 2022, The Author(s).


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