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Series GSE304151 Query DataSets for GSE304151
Status Public on Apr 14, 2026
Title Systems-level investigation of mucopolysaccharidosis IIIA identifies deficient synaptic activity as a key driver of disease progression
Organism Danio rerio
Experiment type Expression profiling by high throughput sequencing
Summary Mucopolysaccharidoses are lysosomal storage diseases that collectively represent a major cause of lethal, treatment-refractory childhood dementias. Clinically-useful interventions are hampered by an incomplete understanding of their neuropathological origins. Using the zebrafish sgshΔex5-6 model of mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome A), we conducted several ‘omics-based analyses to define important features in the progression of neurological disease. We find that the massive endolysosomal burden resulting from increased lysosomal storage of heparan sulfate and other secondarily accumulating substrates induces abnormal microtubule organisation and vesicle trafficking in neurons. This results in a gradual impairment of synaptic vesicle localisation at the presynaptic terminal and consequently impaired neuronal activity. Importantly, the endolysosomal phenotype in MPS IIIA zebrafish precedes the onset of molecular hallmarks of overt synaptic dysfunction, though the larval MPS IIIA brain was found to be more susceptible to perturbation than wild type siblings. Ubiquitous transgenic overexpression of sgsh in sgshΔex5-6 zebrafish corrected neuropathological features at the cellular and molecular level, but was associated with low but elevated rates of developmental malformation. Our findings provide mechanistic evidence linking the well-described lysosomal storage basis for MPS IIIA to its disproportionately neurological manifestations, facilitating development and refinement of future therapeutic interventions for this currently untreatable disorder.
 
Overall design RNA-seq profiling of zebrafish of the following genotypes at the indicated stages/tissues: 1) wild type; 24 hpf whole embryos (n = 50 pooled), 5 dpf larval heads (n = 50 pooled), 2-month-old brain (n = 3 pooled), 3-month-old brain (n = 3 pooled), 18-month-old brain (n = 3 pooled). 2) sgshΔex5-6; 24 hpf whole embryos (n = 50 pooled), 5 dpf larval heads (n = 50 pooled), 2-month-old brain (n = 3 pooled), 3-month-old brain (n = 3 pooled), 18-month-old brain (n = 3 pooled). 3) wild type ubiquitously overexpressing wild type sgsh; 2-month-old brain (n = 3 pooled). 4) sgshΔex5-6 ubiquitously overexpressing wild type sgsh; 2-month-old brain (n = 3 pooled).
 
Contributor(s) Douek AM, Salavaty A, Kaslin J, Ramialison M, Currie PD
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Submission date Jul 31, 2025
Last update date Apr 15, 2026
Contact name Jan Kaslin
E-mail(s) Jan.Kaslin@monash.edu
Organization name Monash University
Department Australian Regenerative Medicine Institute
Lab Kaslin Lab
Street address 15 Innovation Walk
City Melbourne
State/province Victoria
ZIP/Postal code 3800
Country Australia
 
Platforms (2)
GPL29008 DNBSEQ-G400 (Danio rerio)
GPL30277 DNBSEQ-T7 (Danio rerio)
Samples (36)
GSM9144393 24 hpf whole embryo pool (n = 50), sgshΔex5-6 homozygous, rep1
GSM9144394 24 hpf whole embryo pool (n = 50), sgshΔex5-6 homozygous, rep2
GSM9144395 24 hpf whole embryo pool (n = 50), sgshΔex5-6 homozygous, rep3
Relations
BioProject PRJNA1299261

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE304151_RAW.tar 48.9 Mb (http)(custom) TAR (of TXT)
GSE304151_embryo_young_old_counts.star_featureCounts.tsv.gz 3.7 Mb (ftp)(http) TSV
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Raw data are available in SRA
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