Enhanced degradation of synaptophysin by the proteasome in mucopolysaccharidosis type IIIB.

The interruption of the lysosomal degradation of heparan sulfate oligosaccharides has deleterious consequences on the central nervous system in children or in animals with mucopolysaccharidosis type III (Sanfilippo syndrome). Behavioural manifestations are prominent at disease onset, suggesting possible early synaptic defects in cortical neurons. We report that synaptophysin, the most abundant protein of the synaptic vesicle membrane, was detected at low levels in the rostral cortex of MPSIII type B mice as early as 10 days after birth. This defect preceded other disease manifestations, was associated with normal neuron and synapse density and corrected after gene transfer inducing re-expression of the missing lysosomal enzyme. Clearance of heparan sulfate oligosaccharides in cultured embryonic MPSIIIB cortical neurons or treatment with proteasome inhibitors restored normal synaptophysin levels indicating that heparan sulfate oligosaccharides activate the degradation of synaptophysin by the proteasome with consequences on synaptic vesicle components that are relevant to clinical manifestations.