“…Finally, terminal differentiation was achieved through 14 days of neural maturation to generate neurons. Two iPSCs lines from type-3 GD patients carrying the homozygous L444P mutation ( 24 , 25 , GD3-1 and GD3-2, respectively) were utilized in this study, while an iPSCs line from a healthy volunteer ( 29 , Control) served as the control condition. Figure 1 Normal iPSCs and NPCs properties in cells generated by 2 Gaucher disease patients.…”
Section: Resultsmentioning
confidence: 99%
“…This quality makes iPSCs particularly valuable in the study of rare genetic diseases, such as Lysosomal Storage Diseases (LSDs). In our study, we performed an experiment using the two most recently generated iPSCs lines from type-3 Gaucher disease (GD) patients 24 , 25 . These cell lines, derived from type-3 GD patients, exhibited hallmark GD phenotypes, including a reduction in GBA protein expression (Fig.…”
Section: Discussionmentioning
confidence: 99%
“…The iPSCs were cultured according to a previously described protocol using our in-house Essential 8 medium 25 . iPSCs from passages 25–35 were utilized for neural induction.…”
Section: Methodsmentioning
confidence: 99%
“…In this study, we investigated the role of ER stress and dysregulated UPR-mediated apoptosis in nGD using induced pluripotent stem cell (iPSCs)-derived cortical neurons. Our generated iPSCs lines from two type-3 nGD patients who exhibited early signs of neurological involvement 24 , 25 were used in this study. These iPSCs-derived neuronal cells from both GD patients displayed disease phenotypes, including significantly reduced GCase activities and protein levels.…”
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.
“…Finally, terminal differentiation was achieved through 14 days of neural maturation to generate neurons. Two iPSCs lines from type-3 GD patients carrying the homozygous L444P mutation ( 24 , 25 , GD3-1 and GD3-2, respectively) were utilized in this study, while an iPSCs line from a healthy volunteer ( 29 , Control) served as the control condition. Figure 1 Normal iPSCs and NPCs properties in cells generated by 2 Gaucher disease patients.…”
Section: Resultsmentioning
confidence: 99%
“…This quality makes iPSCs particularly valuable in the study of rare genetic diseases, such as Lysosomal Storage Diseases (LSDs). In our study, we performed an experiment using the two most recently generated iPSCs lines from type-3 Gaucher disease (GD) patients 24 , 25 . These cell lines, derived from type-3 GD patients, exhibited hallmark GD phenotypes, including a reduction in GBA protein expression (Fig.…”
Section: Discussionmentioning
confidence: 99%
“…The iPSCs were cultured according to a previously described protocol using our in-house Essential 8 medium 25 . iPSCs from passages 25–35 were utilized for neural induction.…”
Section: Methodsmentioning
confidence: 99%
“…In this study, we investigated the role of ER stress and dysregulated UPR-mediated apoptosis in nGD using induced pluripotent stem cell (iPSCs)-derived cortical neurons. Our generated iPSCs lines from two type-3 nGD patients who exhibited early signs of neurological involvement 24 , 25 were used in this study. These iPSCs-derived neuronal cells from both GD patients displayed disease phenotypes, including significantly reduced GCase activities and protein levels.…”
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.
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