GAP43 overexpression and enhanced neurite outgrowth in mucopolysaccharidosis type IIIB cortical neuron cultures.

Behavioral manifestations mark the onset of disease expression in children with mucopolysaccharidosis type III (MPSIII, Sanfilippo syndrome), a genetic disorder resulting from interruption of the lysosomal degradation of heparan sulfate. In the mouse model of MPSIII type B (MPSIIIB), cortical neuron pathology and dysfunction occur several months before neuronal loss and are primarily cell autonomous. The gene coding for GAP43, a neurite growth potentiator, is overexpressed in the MPSIIIB mouse cortex, and neurite dystrophy was reported in other types of lysosomal storage diseases. We therefore examined the development of the neuritic trees in pure populations of MPSIIIB mouse embryo cortical neurons grown for up to 12 days in primary culture. Dynamic observation of living neurons and quantification of neurite growth parameters indicated more frequent neurite elongation and branching and less frequent neurite retraction, resulting in a relative overgrowth of MPSIIIB neuron neuritic trees, involving both dendrites and axons, compared with normal controls. Neurite overgrowth was concomitant with more than twofold increased expression of GAP43 mRNAs and proteins. Correction of the genetic defect leads to expression of the missing lysosomal enzyme, normal GAP43 mRNA expression, and reduced neurite outgrowth. These results indicate that heparan sulfate oligosaccharide storage modifies GAP43 expression in MPSIIIB cortical neurons with potential consequences for neurite development and neuronal functions that may be relevant to clinical manifestations.