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Patient iPSC-derived brain organoids of neuronopathic Gaucher disease identify imbalances in neural lineages and deficits in interneuron function

ABSTRACT: Gaucher disease is a rare lysosomal storage disorder caused by autosomal recessive mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase. Gaucher disease is classified in 3 different subtypes depending on the presence and severity of neurological affectation, with type 2 resulting in fatal early-onset neuropathology and patients exhibiting developmental delays, seizures and early death. Studies investigating disease mechanisms of neuronopathic Gaucher disease are mainly based on animal models and focus predominantly on late neuronal progression phenotypes. Here, we established a healthy control and Gaucher disease patient iPSC lines and engineered them to obtain isogenic control and disease lines. Using these lines, we generated cortical and subpallial brain organoids in which we identified early-onset lipid dysregulation in form of highly elevated glucosylsphingosine and a posterior increase in gangliosides. Moreover, we uncovered a new phenotype consisting of an increase in more mature inhibitory and excitatory populations at the expnse of a deficit in proliferating and migratory, suggesting a higher susceptibility of specific cell types to Gaucher disease. Interestingly, at the functional level we observed deficits in interneuron function, a clinically significant phenotype as many patients exhibit an excitation/inhibition imbalance leading to treatment-resistant seizures, hastening their decline. In conclusion, our defined human model of Gaucher disease identifies novel and clear phenotypes that can be used for drug screening or aide in development of new therapeutic strategies to ameliorate Gaucher disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300486 | GEO | 2026/02/02

REPOSITORIES: GEO

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Project description:In non-neuronopathic type 1 Gaucher disease (GD1) mutations in GBA1 gene results in deficiency of glucocerebrosidase and the accumulation of glucocerebroside in lysosomes of mononuclear phagocytes. The metabolic defect leads to a complex phenotype involving the viscera, the bone marrow and the skeleton. However the prevailing macrophage-centric view of the disease does not explain emerging aspects of the disease such as hematological malignancies, autoimmune diathesis, ParkinsonM-bM-^@M-^Ys disease and osteoporosis poorly responsive to macrophage targeted enzyme therapy or anti-resorptive therapies. We developed a conditional KO mouse model of GD1 to delineate cells and pathways in GD1. By targeting the cells of the hematopoetic and mesenchymal cell lineages through an Mx1 promoter, we recapitulated human GD1. We show that, in addition to significant visceral and hematologic disease, GD1 mice show profound osteopenia due to a bone formation defect. Cytokine measurements, microarray analysis and cellular immunophenotyping together point to widespread dysfunction of macrophages and other immune cells together with a striking abnormality in thymic T-cell development. Our study provides the first direct evidence for the involvement of cell lineages other than mononuclear phagocytes, most notably osteoblasts and T cells, in the pathophysiology of the clinical spectrum of type 1 GD. These findings have important implications for treatment of GD1. We hypothesize that regulation of gene expression is different in Gaucher disease compared with the normal controls. This difference may even be evident in the different stages of this disease. In order to gain insight to the genes that are potentially involved in the development of Gaucher disease in its different clinical stages, exon-array is chosen for this genome-wide association studies. Mouse liver and spleen samples from normal control, GD with moderate to severe splenomegaly/hepatomegaly, together nine samples were chosen. The goal is to find out genes of which the expression may relate to the GD or the severity of GD and thus help identify genetic modifier genes that may contribute to the onset and development of Gaucher disease.

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Patient iPSC-derived brain organoids of neuronopathic Gaucher disease identify imbalances in neural lineages and deficits in interneuron function

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