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Systems-level investigation of mucopolysaccharidosis IIIA identifies deficient synaptic activity as a key driver of disease progression

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE304151 | GEO | 2026/04/14

REPOSITORIES: GEO

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