Mucopolysaccharidosis type IIIB (MPSIIIB) is a lysosomal storage disease (LSD) characterized by accumulation of heparan sulfate oligosaccharides (HSO), which results in progressive mental retardation, neurodegeneration and premature death in children. The underlying mechanisms are poorly understood. Coming to a better understanding of the pathophysiology of MPSIIIB has become a necessity to assess the efficacy of gene therapy treatment regarding loss of neuronal plasticity, and to define the best conditions for treatment. To address the link between HSO accumulation and downstream pathological events, new cell models of MPSIIIB were created. First, induced pluripotent stem cells (iPSc) were generated from fibroblasts of affected children, followed by differentiation of patient-derived iPSc into a neuronal progeny. Second, a HeLa cell model was created in which expression of shRNAs directed against a-N-acetylglucosaminidase (NAGLU), the deficient enzyme in MPSIIIB, is induced by tetracycline. Success in the isolation of these different models was pointed by the presence of cardinal features of MPSIIIB cell pathology. Studies in these models showed that: I) HSO excreted in the extracellular matrix modifies cell perception of environmental cues, affecting downstream signalling pathways with consequences on the Golgi morphology. II) Accumulation of intracellular storage vesicles, a hallmark of LSDs is due to overexpression of the cis-Golgi protein GM130 and subsequent Golgi alterations. It is likely that these vesicles are abnormal lysosomes formed in the cis- and medial-Golgi which are misrouted at an early step of lysosome biogenesis, giving rise to a dead-end compartment. III) Other cell functions controlled by GM130 are affected, including centrosome morphology and microtubule nucleation. These data point to possible consequences on cell polarization, cell migration and neuritogenesis.
