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Iron supplementation in zebrafish models of mucopolysaccharidoses type III

ABSTRACT: Sanfilippo Syndrome Type B, characterized by a deficiency in N-acetylglucosaminidase (NAGLU) enzyme, represents a debilitating genetic disorder which causes childhood dementia. In this study, we employed zebrafish models carrying the naglu A603fs mutation to investigate the potential of intraperitoneal (i.p.) injection of ferric citrate to rescue whole brain transcriptomes relative to an i.p. injection of saline vehicle control. Zebrafish, aged 6 months, were either homozygous (MPS IIIB) and heterozygous (unaffected control) genotypes, and each group was subjected to either ferric citrate or saline injection. A total of 10 fish per genotype and treatment were examined via RNA-seq. Although initial findings identified sex-specific differences in inflammation pathways and regeneration which may be rescued in female samples (but not in males), the sample size of fish per genotype, sex, and treatment limited the ability to draw definitive conclusions.

ORGANISM(S): Danio rerio

PROVIDER: GSE241596 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Sanfilippo syndrome type B (MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu -/- and Naglu +/- mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu -/- mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments - P-tau aggregates characteristic of tauopathies, a group of age-related dementias that includes Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy. Two-condition experiment, Naglu-/- (affected) vs. Naglu+/- (unaffected control) of neurons from two adjacent brain regions: medial entorhinal cortex (MEC) and lateral entorhinal cortex (LEC). Biological replicates: 3 MEC Naglu-/-, 3 MEC Naglu+/-, 3 LEC Naglu-/- and 3 LEC Naglu+/-. Comparisons were made between 3 pairs of mutant and control female littermates for MEC and LEC neurons with dye switch duplicates, for a total of 12 microarrays.

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Iron supplementation in zebrafish models of mucopolysaccharidoses type III

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