An increase in ER stress and unfolded protein response in iPSCs-derived neuronal cells from neuronopathic Gaucher disease patients.

ER stress Gaucher disease LSDs UPR iPSCs-derived neurons

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
22 Apr 2024
Historique:
received: 31 01 2024
accepted: 16 04 2024
medline: 23 4 2024
pubmed: 23 4 2024
entrez: 22 4 2024
Statut: epublish

Résumé

Gaucher disease (GD) is a lysosomal storage disorder caused by a mutation in the GBA1 gene, responsible for encoding the enzyme Glucocerebrosidase (GCase). Although neuronal death and neuroinflammation have been observed in the brains of individuals with neuronopathic Gaucher disease (nGD), the exact mechanism underlying neurodegeneration in nGD remains unclear. In this study, we used two induced pluripotent stem cells (iPSCs)-derived neuronal cell lines acquired from two type-3 GD patients (GD3-1 and GD3-2) to investigate the mechanisms underlying nGD by biochemical analyses. These iPSCs-derived neuronal cells from GD3-1 and GD3-2 exhibit an impairment in endoplasmic reticulum (ER) calcium homeostasis and an increase in unfolded protein response markers (BiP and CHOP), indicating the presence of ER stress in nGD. A significant increase in the BAX/BCL-2 ratio and an increase in Annexin V-positive cells demonstrate a notable increase in apoptotic cell death in GD iPSCs-derived neurons, suggesting downstream signaling after an increase in the unfolded protein response. Our study involves the establishment of iPSCs-derived neuronal models for GD and proposes a possible mechanism underlying nGD. This mechanism involves the activation of ER stress and the unfolded protein response, ultimately leading to apoptotic cell death in neurons.

Identifiants

DOI: 10.1038/s41598-024-59834-6 PMID: 38649404
pubmed: 38649404
doi: 10.1038/s41598-024-59834-6
pii: 10.1038/s41598-024-59834-6
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

9177

Subventions

Organisme : Mahidol University
ID : MU-MiniRC12/2565

Informations de copyright

© 2024. The Author(s).

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Auteurs

Tanapat Pornsukjantra (T)

Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.

Nongluk Saikachain (N)

Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Pla, Bang Phli, Samut Prakan, 10540, Thailand.

Nareerat Sutjarit (N)

Graduate Program in Nutrition, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.

Arthaporn Khongkrapan (A)

Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.

Alisa Tubsuwan (A)

Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand.

Kanit Bhukhai (K)

Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.

Thipwimol Tim-Aroon (T)

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.

Usanarat Anurathapan (U)

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.

Suradej Hongeng (S)

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.

Nithi Asavapanumas (N)

Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Pla, Bang Phli, Samut Prakan, 10540, Thailand. nithi.asa@mahidol.edu.

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