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A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation
Author(s) -
Son MiYoung,
Kwak Jae Eun,
Seol Binna,
Lee Da Yong,
Jeon Hyejin,
Cho Yee Sook
Publication year - 2015
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4551
Subject(s) - induced pluripotent stem cell , neurodegeneration , biology , inflammasome , microbiology and biotechnology , neural stem cell , stem cell , phenotype , gene , embryonic stem cell , immunology , disease , genetics , medicine , pathology , inflammation
GM1 gangliosidosis ( GM1 ) is an inherited neurodegenerative disorder caused by mutations in the lysosomal β‐galactosidase (β‐gal) gene. Insufficient β‐gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell ( iPSC ) technology. Neural progenitor cells differentiated from GM1 patient‐derived iPSCs ( GM1‐NPCs ) recapitulated the biochemical and molecular phenotypes of GM1 , including defective β‐gal activity and increased lysosomes. Importantly, the characterization of GM1‐NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease‐related phenotypes of GM1‐NPCs in vitro and in vivo . Our data demonstrate that GM1‐NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.