PUBLICATION

A zebrafish model of Combined Saposin Deficiency identifies acid sphingomyelinase as a potential therapeutic target

Authors
Zhang, T., Alonzo, I., Stubben, C., Geng, Y., Herdman, C., Chandler, N., Doane, K.P., Pluimer, B.R., Trauger, S.A., Peterson, R.T.
ID
ZDB-PUB-230515-40
Date
2023
Source
Disease models & mechanisms   16(7): (Journal)
Registered Authors
Peterson, Randall
Keywords
Lipidomics, Lysosomal storage disease, Zebrafish
Datasets
GEO:GSE227551
MeSH Terms
  • Sphingolipidoses*
  • Sphingomyelin Phosphodiesterase/genetics
  • Animals
  • Saposins/genetics
  • Zebrafish/metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Lysosomal Storage Diseases*
(all 7)
PubMed
37183607 Full text @ Dis. Model. Mech.
Abstract
Sphingolipidoses are a subcategory of lysosomal storage diseases (LSDs) caused by mutations in enzymes of the sphingolipid catabolic pathway. Like many LSDs, neurological involvement in sphingolipidoses leads to early mortality with limited treatment options. Given the role of myelin loss as a major contributor toward LSD-associated neurodegeneration, we investigated the pathways contributing to demyelination in a CRISPR-Cas9 zebrafish model of Combined Saposin Deficiency (psap). psap zebrafish recapitulated major LSD pathologies including reduced lifespan, lipid storage, impaired locomotion, and severe myelin loss; loss of myelin basic protein a (mbpa) mRNA was progressive with no changes in additional markers of oligodendrocyte differentiation. Brain transcriptomics revealed dysregulated mTORC1 signaling and elevated neuroinflammation, where increased proinflammatory cytokine expression preceded and mTORC1 signaling changes followed mbpa loss. We examined pharmacological and genetic rescue strategies via 1) water tank administration of the multiple sclerosis drug monomethylfumarate (MMF), and 2) crossing the psap line into an acid sphingomyelinase deficiency (smpd1) model.1,2 Smpd1 mutagenesis, but not MMF, prolonged lifespan in psap zebrafish, highlighting the modulation of acid sphingomyelinase activity as a potential path toward sphingolipidosis treatment.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
f28
    		Complex
    f29
      		Complex
      f30
        		Indel
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        psapCRISPR3-psapCRISPR
        psapCRISPR4-psapCRISPR
        psapCRISPR5-psapCRISPR
        psapCRISPR1-psapCRISPR
        psapCRISPR2-psapCRISPR
        smpd1CRISPR3-smpd1CRISPR
        smpd1CRISPR4-smpd1CRISPR
        smpd1CRISPR5-smpd1CRISPR
        smpd1CRISPR6-smpd1CRISPR
        smpd1CRISPR7-smpd1CRISPR
        1 - 10 of 10
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        Fish
        No data available
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        No data available
        Mapping
        No data available
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        Citation
        Zhang, T., Alonzo, I., Stubben, C., Geng, Y., Herdman, C., Chandler, N., Doane, K.P., Pluimer, B.R., Trauger, S.A., Peterson, R.T. (2023) A zebrafish model of Combined Saposin Deficiency identifies acid sphingomyelinase as a potential therapeutic target. Disease models & mechanisms. 16(7):.