Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Laura E. Kuil, Anna López Martí, Ana Carreras Mascaro, Jeroen C. van den Bosch, Paul van den Berg, Herma C. van der Linde, Kees Schoonderwoerd, George J. G. Ruijter, Tjakko J. van Ham

Research output: Contribution to JournalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1705-1718
Issue number9
Publication statusPublished - 1 Sept 2019
Externally publishedYes


We thank Dr. Gerben Schaaf for valuable feedback on the manuscript, Dr. Nynke Oosterhof for developing an ImageJ macro for LT quantification, and Dr. Marco Morsch (Macquarie University, Sydney) for providing the Ubi:SecA5-mVenus plasmid. The members of the Erasmus MC Optical Imaging Center (OIC) are acknowledged for assistance on microscopy. This work was sponsored by a ZonMW VENI grant and an Erasmus University Rotterdam fellowship to TJvH.

FundersFunder number
Macquarie UniversitySydney
Erasmus Universiteit Rotterdam
Erasmus Medisch Centrum


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