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

Human infantile-onset RNASET2 deficient cystic leukoencephalopathy is a Mendelian mimic of in utero cytomegalovirus brain infection with prenatally developing inflammatory brain lesions. We used a RNASET2 deficient zebrafish model to elucidate the underlying disease mechanisms. Mutant and wildtype zebrafish larvae brain development between 2 and 5 days post fertilisation was examined by confocal live imaging in fluorescent reporter lines of 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 first insight 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-Goutieres syndrome (AGS).