An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA

Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgsh^Δex5−6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgsh^Δex5−6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgsh^Δex5−6 zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgsh^Δex5−6 mutant larvae in a context-dependent manner. We expect the sgsh^Δex5−6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions.     

Lead contamination of an old shooting range affecting the local ecosystem--A case study with a holistic approach

The aim of this case study was to uncover the consequences of lead pellet-derived heavy lead contamination at a cast-off shooting range in southern Finland, covering aspects from soil chemistry and biology up to ecosystem level. The observed changes in the soil properties of the most contaminated areas suggest that the contamination may be disturbing processes of decomposition and nutrient mineralisation. Also two functionally important groups of soil organisms, microbes (as analysed using the PLFA analysis) and enchytraeid worms, were negatively affected by the contamination. Furthermore, there was an indication of reduced pine litter production at the contaminated areas. On the other hand, lead contamination appears not to have affected pine growth or soil-dwelling nematodes and microarthropods, and the general outlook of the whole ecosystem is that of a healthy forest. Thus, the boreal forest ecosystem studied as a whole appears to bear strong resistance to contamination, despite negative effects of lead on many of its components. This resistance may result from e.g. low bioavailability of lead, avoidance of the most contaminated soil horizons and microsites by the organisms, and functional redundancy and development of lead-tolerant populations amongst the organisms. The relative importance of these factors and the mechanisms behind them will be investigated in forthcoming studies.