A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation.
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.
Stem Cell Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea.
Mi-Young
MY
Son
Stem Cell Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
Jae Eun
JE
Kwak
Stem Cell Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
Binna
B
Seol
Stem Cell Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
Da Yong
DY
Lee
Stem Cell Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
Hyejin
H
Jeon
Stem Cell Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea.
Yee Sook
YS
Cho
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D048430:Cell Shape; D065150:Cellular Reprogramming; D016537:Gangliosidosis, GM1 / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D001616:beta-Galactosidase / Q000378:metabolism
D015415:Biomarkers; D007155:Immunologic Factors; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D001616:beta-Galactosidase
GM1 gangliosidosis; human disease model; induced pluripotent stem cells; inflammasome; neural progenitor cells