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Title: Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells
Authors: Julianna Kobolák
Kinga Molnár
Eszter Varga
István Bock
Bálint Jezsó
Annamária Téglási
Shuling Zhou
Maria Lo Giudice
Marianne Hoogeveen-Westerveld
WWM Pim Pijnappel
Phetcharat Phanthong
Norbert Varga
Narisorn Kitiyanant
Kristine Freude
Hideyuki Nakanishi
Lajos László
Poul Hyttel
András Dinnyés
BioTalentum Ltd.
Erasmus MC
Kyoto Institute of Technology
Københavns Universitet
Heim Pál Children's Hospital
Szent István Egyetem
Eötvös Loránd University
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 15-Jul-2019
Citation: Experimental Cell Research. Vol.380, No.2 (2019), 216-233
Abstract: © 2019 The Authors Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder (LSD), caused by iduronate 2-sulphatase (IDS) enzyme dysfunction. The neuropathology of 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 LAMP2 expression but unchanged in their RAB7 compartment. Based on these finding we hypothesize that lysosomal membrane protein (LMP) carrier vesicles have an initiating role in the formation of storage vacuoles leading to impaired lysosomal function. In conclusion, a novel human MPS II disease model was established for the first time which recapitulates the in vitro neuropathology of the disorder, providing novel information on the disease mechanism which allows better understanding of further lysosomal storage disorders and facilitates drug testing and gene therapy approaches.
ISSN: 10902422
Appears in Collections:Scopus 2019

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