AI Article Synopsis
- Gaucher disease (GD) is linked to mutations in the GBA1 gene, leading to insufficient acid β-glucosidase activity, which causes issues in neuron development and function.
- Research utilized induced pluripotent stem cells (iPSCs) from GD type 2 (GD2) patients to investigate how these mutations affect neurons, revealing a deficiency in GCase and an accumulation of specific lipids, which are related to the disease.
- The study found that GD2 neurons exhibit abnormal electrophysiological properties, such as less negative resting membrane potentials and reduced action potential amplitudes, indicating that these alterations may contribute to the neurological symptoms associated with Gaucher disease.
Article Abstract
Gaucher disease (GD) is caused by insufficient activity of acid β-glucosidase (GCase) resulting from mutations in GBA1. To understand the pathogenesis of the neuronopathic GD, induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from three GD type 2 (GD2) and 2 unaffected (normal and GD carrier) individuals. The iPSCs were converted to neural precursor cells (NPCs) which were further differentiated into neurons. Parental GD2 fibroblasts as well as iPSCs, NPCs, and neurons had similar degrees of GCase deficiency. Lipid analyses showed increases of glucosylsphingosine and glucosylceramide in the GD2 cells. In addition, GD2 neurons showed increased α-synuclein protein compared to control neurons. Whole cell patch-clamping of the GD2 and control iPSCs-derived neurons demonstrated excitation characteristics of neurons, but intriguingly, those from GD2 exhibited consistently less negative resting membrane potentials with various degree of reduction in action potential amplitudes, sodium and potassium currents. Culture of control neurons in the presence of the GCase inhibitor (conduritol B epoxide) recapitulated these findings, providing a functional link between decreased GCase activity in GD and abnormal neuronal electrophysiological properties. To our knowledge, this study is first to report abnormal electrophysiological properties in GD2 iPSC-derived neurons that may underlie the neuropathic phenotype in Gaucher disease.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378893 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118771 | PLOS |
Publication Analysis
Top Keywords
Similar Publications
A Case of Hodgkin Lymphoma in a Gaucher Disease Patient: Distinguishing Gaucher and Pseudo-Gaucher Cells.
Am J Hematol
January 2025
Dipartimento di Scienze Cliniche e di Comunità, Dipartimento di Eccellenza 2023-2027, University of Milan, Milan, Italy.
Recently, a novel African ancestry specific Parkinson's disease (PD) risk signal was identified at the gene encoding glucocerebrosidase ( ). This variant (rs3115534-G) is carried by ∼50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups, but is almost absent in European and Asian ancestry populations.
View Article and Find Full Text PDFDeveloping Allosteric Chaperones for -Associated Disorders-An Integrated Computational and Experimental Approach.
Int J Mol Sci
December 2024
Gain Therapeutics Sucursal en España, Parc Científic de Barcelona, 08028 Barcelona, Spain.
Mutations in the gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson's disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring mutations.
View Article and Find Full Text PDFRare of Gaucher's Disease Complication of Splenic Multiple Gaucheroma.
Endocr Metab Immune Disord Drug Targets
January 2025
Department of Endocrinology and Metabolic Diseases, Erciyes University Faculty of Medicine, Kayseri, Turkey.
Background: Gaucheromas, pseudotumors composed of Gaucher cells, are rare complications of Gaucher's Disease (GD). They are usually seen in patients receiving enzyme replacement. Surgery is generally not recommended for these benign masses in treatment management.
View Article and Find Full Text PDFPredicting liver fibrosis in Gaucher disease: Investigation of contributors and development of a clinically applicable Gaucher liver fibrosis score.
Mol Genet Metab
January 2025
Medical Genetics Service, HCPA, UFRGS, Porto Alegre, RS, Brazil; Graduate Program in Genetics and Molecular Biology, UFRGS, Porto Alegre, RS, Brazil; InRaras (National Institute of Science and Technology on Rare Diseases), Brazil.
Gaucher disease (GD) is a rare genetic disorder with multi-system involvement. Liver fibrosis is a long-term complication of GD, potentially leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. There are currently no validated clinical tools for the monitoring of liver fibrosis in patients with GD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!