Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells

Abstract Mucopolysaccharidosis II(MPS II) is a lysosomal storage disorder(LSD), caused by iduronate 2-sulphatase (IDS) enzyme dysfunction. The neuropathologyof the disease is not well understood, although the neural symptoms are currently incurable. MPS II-patient derived iPSC lines were established and differentiated to neuronal lineage. The disease phenotype was confirmed by IDS enzyme and glycosaminoglycan assay. MPS II neuronal precursor cells (NPCs) showed significantly decreased self-renewal capacity, while their cortical neuronal differentiation potential was not affected. Major structural alterations in the ER and Golgi complex, accumulation of storage vacuoles, and increased apoptosis were observed both at protein expression and ultrastructural level in the MPS II neuronal cells, which was more pronounced in GFAP + astrocytes, with increased LAMP2expression but unchanged in their RAB7 compartment. Based on these finding we hypothesize that lysosomalmembrane protein (LMP) carrier vesicles have an initiating role in the formation of storage vacuoles leading to impaired lysosomalfunction. In conclusion, a novel human MPS II disease model was established for the first time which recapitulates the in vitro neuropathologyof the disorder, providing novel information on the disease mechanism which allows better understanding of further lysosomal storage disordersand facilitates drug testingand gene therapy approaches.