Abstract
Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β‐Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/−) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb −/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/−) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non‐neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.
Highlights
Lysosomal storage disorders (LSDs) comprise a group of at least 55 disorders, which are caused by genetic mutations in lysosomal enzymes leading to loss of protein function (Kielian, 2019)
Already within 5 days of development, hexb−/− larvae presented with abnormal lysosomes in microglia and in radial glia
Based on our zebrafish model, the early presentation of abnormal lysosomes in glial cells implies that pathogenesis might be characterized by dysfunctional glial cells in the first stages of standard deviation (SD)
Summary
Lysosomal storage disorders (LSDs) comprise a group of at least 55 disorders, which are caused by genetic mutations in lysosomal enzymes leading to loss of protein function (Kielian, 2019). SD patient IPS cell-derived organoids showed aberrant neuronal differentiation (Allende et al, 2018) These studies suggest that HEXB deficiency could intrinsically affect neuronal differentiation and induce increased astrocyte numbers, which could be an initiating event in the pathogenesis of SD. Immune suppression or bone marrow transplantations improve neurological function in SD mice, likely by reducing gliosis (Abo-Ouf et al, 2013; Ogawa et al, 2017; Ogawa et al, 2018; Wada et al, 2000; Wu, Mizugishi, Bektas, Sandhoff, & Proia, 2008) These therapies seem very promising, it is important to understand to what extent such approaches are targeting the cause, rather than inhibiting the symptoms. We identified some of the cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations
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