TY - JOUR
T1 - Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish
AU - Lelieveld, Lindsey T.
AU - Gerhardt, Sophie
AU - Maas, Saskia
AU - Zwiers, Kimberley C.
AU - de Wit, Claire
AU - Beijk, Ernst H.
AU - Ferraz, Maria J.
AU - Artola, Marta
AU - Meijer, Annemarie H.
AU - Tudorache, Christian
AU - Salvatori, Daniela
AU - Boot, Rolf G.
AU - Aerts, Johannes M. F. G.
N1 - Funding Information: Joost Willemse is kindly acknowledged for the ImageJ plugin to quantify the length and tortuosity of individual zebrafish. Wouter Bax is kindly acknowledged for his work on studying zebrafish Asah1a and Asah1b in vitro. We thank Ulrike Nehrdich, Guus van der Velden, and Ruth van Koppen for their overall expertise and particularly for their help in monitoring the mutant zebrafish. The study was supported by the NWO BBOL 2018 (737.016.022) grant. Publisher Copyright: © 2022 THE AUTHORS.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - In Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph) in the lysosome. Chronically elevated blood and tissue GlcSph is thought to contribute to symptoms in GD patients as well as to increased risk for Parkinson’s disease. On the other hand, formation of GlcSph may be beneficial since the water soluble sphingoid base is excreted via urine and bile. To study the role of excessive GlcSph formation during glucocerebrosidase deficiency, we studied zebrafish that have two orthologs of acid ceramidase, Asah1a and Asah1b. Only the latter is involved in the formation of GlcSph in glucocerebrosidase-deficient zebrafish as revealed by knockouts of Asah1a or Asah1b with glucocerebrosidase deficiency (either pharmacologically induced or genetic). Comparison of zebrafish with excessive GlcSph (gba1-/- fish) and without GlcSph (gba1-/-:asah1b-/- fish) allowed us to study the consequences of chronic high levels of GlcSph. Prevention of excessive GlcSph in gba1-/-:asah1b-/- fish did not restrict storage cells, GlcCer accumulation, or neuroinflammation. However, GD fish lacking excessive GlcSph show an ameliorated course of disease reflected by significantly increased lifespan, delayed locomotor abnormality, and delayed development of an abnormal curved back posture. The loss of tyrosine hydroxylase 1 (th1) mRNA, a marker of dopaminergic neurons, is slowed down in brain of GD fish lacking excessive GlcSph. In conclusion, in the zebrafish GD model, excess GlcSph has little impact on (neuro)inflammation or the presence of GlcCer-laden macrophages but rather seems harmful to th1-positive dopaminergic neurons.
AB - In Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph) in the lysosome. Chronically elevated blood and tissue GlcSph is thought to contribute to symptoms in GD patients as well as to increased risk for Parkinson’s disease. On the other hand, formation of GlcSph may be beneficial since the water soluble sphingoid base is excreted via urine and bile. To study the role of excessive GlcSph formation during glucocerebrosidase deficiency, we studied zebrafish that have two orthologs of acid ceramidase, Asah1a and Asah1b. Only the latter is involved in the formation of GlcSph in glucocerebrosidase-deficient zebrafish as revealed by knockouts of Asah1a or Asah1b with glucocerebrosidase deficiency (either pharmacologically induced or genetic). Comparison of zebrafish with excessive GlcSph (gba1-/- fish) and without GlcSph (gba1-/-:asah1b-/- fish) allowed us to study the consequences of chronic high levels of GlcSph. Prevention of excessive GlcSph in gba1-/-:asah1b-/- fish did not restrict storage cells, GlcCer accumulation, or neuroinflammation. However, GD fish lacking excessive GlcSph show an ameliorated course of disease reflected by significantly increased lifespan, delayed locomotor abnormality, and delayed development of an abnormal curved back posture. The loss of tyrosine hydroxylase 1 (th1) mRNA, a marker of dopaminergic neurons, is slowed down in brain of GD fish lacking excessive GlcSph. In conclusion, in the zebrafish GD model, excess GlcSph has little impact on (neuro)inflammation or the presence of GlcCer-laden macrophages but rather seems harmful to th1-positive dopaminergic neurons.
KW - Supplementary key words Gaucher disease
KW - acid ceramidase
KW - dopaminergic neurons
KW - glucosylceramide
KW - lipid metabolism
KW - lysosphingolipids
KW - sphingolipids
KW - zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85129411188&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jlr.2022.100199
DO - https://doi.org/10.1016/j.jlr.2022.100199
M3 - Article
C2 - 35315333
SN - 0022-2275
VL - 64
JO - Journal of lipid research
JF - Journal of lipid research
IS - 5
M1 - 100199
ER -