Zebrafish models of Mucopolysaccharidosis types IIIA, B, & C show hyperactivity and changes in oligodendrocyte state

Abstract

Sanfilippo syndrome childhood dementia, also known as mucopolysaccharidosis type III (MPS III), is a rare inherited lysosomal storage disorder. Subtypes of MPS III are caused by deficiencies in one of four enzymes required for degradation of the glycosaminoglycan heparan sulfate (HS). An inability to degrade HS leads to progressive neurodegeneration and death in the second or third decades of life. Knowledge of MPS III pathogenesis is incomplete, and no effective therapies exist. We generated the hypomorphic mutationssgshS387Lfs,nagluA603EfsandhgsnatG577Sfsin the endogenous zebrafish genes orthologous to humanSGSH,NAGLU, andHGSNATthat are loci for mutations causing MPS III subtypes MPS IIIA, B and C respectively. Our models display the primary MPS III disease signature of significant brain accumulation of HS, while behavioural analyses support hyperactivity phenotypes. Brain transcriptome analysis revealed changes related to lysosomal, glycosaminoglycan, immune system and iron homeostasis biology in all three models but also distinct differences in brain transcriptome state between models. The transcriptome analysis also indicated marked disturbance of the oligodendrocyte cell state in the brains of MPS IIIA, B and C zebrafish, supporting that effects on this cell type are an early and consistent characteristic of MPS III. Overall, our zebrafish models recapture key characteristics of the human disease and phenotypes seen in mouse models. Our models will allow exploitation of the zebrafish’s extreme fecundity and accessible anatomy to dissect the pathological mechanisms both common and divergent between the MPS IIIA, B, and C subtypes.

Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms

“…We sought to compare directly the changes in global gene expression occurring due to heterozygosity for an EOfAD-like mutation in psen1 ( psen1 Q96_K97del ) or homozygosity for loss-of-function mutations in naglu ( naglu A603fs , i.e. causing MPS IIIB (41)) in 7 dpf zebrafish larvae using RNA-seq. First, to assess the overall similarity between samples, we used principal component analysis (PCA).…”

“…The generation of the naglu A603fs and psen1 Q96_K97del lines of zebrafish used in this study was described in (41) and (43) respectively. All fish were maintained and raised in a recirculating water system with a constant temperature of approximately 26°C, salinity levels at approximately 300 ppm, and conductivity approximately 800 µS/cm.…”

“…Zebrafish genetic models have emerged as powerful tools for studying cellular/molecular phenomena in neurodegenerative diseases, particularly due to their ∼70% genetic similarity to humans (34) and their high fecundity (reviewed in (35)). We have previously generated several zebrafish knock-in models of mutations causing early-onset familial AD (36–40) and MPS III (41) and has analysed their brain transcriptomes. We have noted that all the models of both diseases exhibit differential expression of genes involved in metabolic pathways (41, 42).…”

“…We have previously generated several zebrafish knock-in models of mutations causing early-onset familial AD (36–40) and MPS III (41) and has analysed their brain transcriptomes. We have noted that all the models of both diseases exhibit differential expression of genes involved in metabolic pathways (41, 42). The most sensitive comparisons of these disease models is best done within single zebrafish families, where genetic and environmental variation is reduced between experimental groups of interest.…”

“…Here, we use intra-family analyses to compare the gene expression profiles of a zebrafish model of EOfAD; psen1 Q96_K97del (43), with that of naglu A603fs , a model of MPS IIIB (41). We performed our analyses at two ages: 7 days post fertilisation (dpf) which models very early, pre-symptomatic stages for both diseases, and in young adult brains (6 months of age), which still models pre-symptomatic disease stages for EOfAD but is symptomatic for MPS IIIB.…”