TY - JOUR
T1 - Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells
AU - Kobolák, Julianna
AU - Molnár, Kinga
AU - Varga, Eszter
AU - Bock, István
AU - Jezsó, Bálint
AU - Téglási, Annamária
AU - Zhou, Shuling
AU - Lo Giudice, Maria
AU - Hoogeveen-Westerveld, Marianne
AU - Pijnappel, WWM Pim
AU - Phanthong, Phetcharat
AU - Varga, Norbert
AU - Kitiyanant, Narisorn
AU - Freude, Kristine
AU - Nakanishi, Hideyuki
AU - László, Lajos
AU - Hyttel, Poul
AU - Dinnyés, András
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Autophagy
KW - Endosomal-lysosomal system
KW - iPSC
KW - Mucopolysaccharidosis II
KW - Neuronal
KW - Storage vacuoles
U2 - 10.1016/j.yexcr.2019.04.021
DO - 10.1016/j.yexcr.2019.04.021
M3 - Journal article
C2 - 31039347
AN - SCOPUS:85065119549
SN - 0014-4827
VL - 380
SP - 216
EP - 233
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 2
ER -
