Gene expression changes in Tay-Sachs disease begin early in fetal brain development

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Monogenic disorders often lack targeted treatments, relying on symptomatic management.
• Gene therapy presents a potential curative approach, especially for pre-symptomatic interventions.
• Tay-Sachs disease (TSD) is a candidate for pre-symptomatic treatment, but its early stages are poorly understood.

Purpose of the Study:

• To investigate the molecular and developmental effects of TSD in the human fetal brain.
• To identify transcriptomic changes associated with biallelic pathogenic variants in the HEXA gene.
• To understand the pre-symptomatic pathology of TSD to inform early therapeutic strategies.

Main Methods:

• Analysis of transcriptomes from human fetal brain samples with HEXA pathogenic variants.
• Comparative analysis of gene expression profiles between affected and unaffected fetal brains.
• Investigation of sphingolipid metabolic pathway alterations.

Main Results:

• Significant alterations in the fetal brain transcriptome indicate perturbed development in TSD.
• A shift in sphingolipid metabolism was observed, potentially compensating for HEXA enzyme dysfunction.
• Absence of end-stage disease transcriptomic signatures suggests developmental issues precede neurodegeneration.

Conclusions:

• Fetal TSD brain development is dramatically altered, with perturbations preceding neurodegeneration.
• Understanding pre-symptomatic TSD pathology is crucial for setting expectations for early gene therapy interventions.
• This study provides the first gene expression analysis of fetal TSD tissues, offering insights into juvenile onset TSD.