PUBLICATION

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

Authors
Kuil, L.E., López Martí, A., Carreras Mascaro, A., van den Bosch, J.C., van den Berg, P., van der Linde, H.C., Schoonderwoerd, K., Ruijter, G.J.G., van Ham, T.J.
ID
ZDB-PUB-190530-9
Date
2019
Source
Glia   67(9): 1705-1718 (Journal)
Registered Authors
Kuil, Laura, van der Linde, Herma, van Ham, Tjakko
Keywords
brain disease, glia, hexb deficiency, in vivo imaging, zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis/physiology
  • Brain/enzymology*
  • Brain/growth & development*
  • Brain/pathology
  • Disease Models, Animal
  • Lysosomes/enzymology*
  • Lysosomes/pathology
  • Motor Activity/physiology
  • Neuroglia/enzymology*
  • Neuroglia/pathology
  • Sphingolipidoses/enzymology
  • Zebrafish
  • beta-Hexosaminidase beta Chain/genetics*
PubMed
31140649 Full text @ Glia
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.
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Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping