Zebrafish disease model of human RNASET2-deficient cystic leukoencephalopathy displays abnormalities in early microglia

• Published in: Biology open Vol. 9; no. 5
• Main Authors: Weber, Thomas, Schlotawa, Lars, Dosch, Roland, Hamilton, Noémie, Kaiser, Jens, Schiller, Stina, Wenske, Britta, Gärtner, Jutta, Henneke, Marco
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 07-05-2020; The Company of Biologists
• Subjects: Abnormalities; Animals; Apoptosis; Brain; Cell lineage; Children; Congenital diseases; cystic leukoencephalopathy; Cytomegalovirus; Danio rerio; Disease; Disease Susceptibility; Fertilization; Fluorescence; Genetic Association Studies - methods; Genetic Predisposition to Disease; Genotype & phenotype; Glial stem cells; Humans; Hypotheses; Immune system; Inclusions; Infections; Inflammation; innate immune system; Innate immunity; Larva; Larvae; Leukoencephalopathies - diagnosis; Leukoencephalopathies - genetics; Leukoencephalopathies - metabolism; Leukoencephalopathy; Lysosomes; Medical research; Microglia; Microglia - metabolism; Morphology; Mutation; Neuroimaging; Neurons; Neurons - metabolism; Organogenesis - genetics; Phenotype; Rhombencephalon - abnormalities; Rhombencephalon - embryology; Rhombencephalon - metabolism; Ribonucleases - deficiency; rnaset2; Tumor Suppressor Proteins - deficiency; Zebrafish; Lysosomes; Zebrafish; Innate immune system; Cystic leukoencephalopathy; RNASET2
• ISSN: 2046-6390; 2046-6390
• DOI: 10.1242/bio.049239

Human infantile-onset RNASET2-deficient cystic leukoencephalopathy is a Mendelian mimic of
cytomegalovirus brain infection with prenatally developing inflammatory brain lesions. We used an RNASET2-deficient zebrafish model to elucidate the underlying disease mechanisms. Mutant and wild-type zebrafish larvae brain development between 2 and 5 days post fertilization (dpf) was examined by confocal live imaging in fluorescent reporter lines of the major types of brain cells. In contrast to wild-type brains, RNASET2-deficient larvae displayed increased numbers of microglia with altered morphology, often containing inclusions of neurons. Furthermore, lysosomes within distinct populations of the myeloid cell lineage including microglia showed increased lysosomal staining. Neurons and oligodendrocyte precursor cells remained unaffected. This study provides a first look into the prenatal onset pathomechanisms of human RNASET2-deficient leukoencephalopathy, linking this inborn lysosomal disease to the innate immune system and other immune-related childhood encephalopathies like Aicardi-Goutières syndrome (AGS).