Identifying altered developmental pathways in human globoid cell leukodystrophy iPSCs-derived NSCs using...

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Globoid cell leukodystrophy (GLD) is a severe neurodegenerative disorder characterized by demyelination due to galactocerebrosidase defects.
• Molecular mechanisms of GLD in human neural cells remain poorly understood.
• Patient-derived induced pluripotent stem cells (iPSCs) offer a valuable model for studying GLD.

Purpose of the Study:

• Investigate gene-expression changes in GLD patient-derived iPSCs and neural stem cells (NSCs).
• Identify molecular pathways contributing to GLD pathogenesis.
• Validate the utility of iPSC-based models for GLD research.

Main Methods:

• Comparison of gene expression profiles between GLD patient (K-iPSCs/NSCs) and control (AF-iPSCs/NSCs) using RNA-sequencing.
• Identification of significantly dysregulated messenger RNAs (mRNAs).
• Validation of differentially expressed genes using real-time quantitative polymerase chain reaction (RT-qPCR).

Main Results:

• Identified 194 dysregulated mRNAs in K-iPSCs vs. AF-iPSCs and 702 in K-NSCs vs. AF-NSCs.
• Enriched Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways related to GLD.
• Validated 25 differentially expressed genes and identified pathways in neuroactive ligand-receptor interactions, synaptic signaling, and cell signaling.

Conclusions:

• Mutations in the galactosylceramidase gene disrupt identified signaling pathways during neural development, contributing to GLD.
• The iPSC-based model (K-iPSCs) serves as a novel tool for studying the molecular basis of GLD.