GBA1 Gene-Associated Transcriptomic Signatures Reveal Risk Genes in Parkinson's Disease.

Area of Science:

• Genetics and Genomics
• Neuroscience
• Systems Biology

Background:

• Pathogenic variants in the GBA1 gene, encoding β-glucocerebrosidase, are a major genetic risk factor for Parkinson's disease (PD).
• Variable PD penetrance among GBA1 variant carriers suggests the involvement of additional genetic and molecular modifiers.
• Investigating shared transcriptomic alterations between Gaucher disease (GD) and PD can elucidate mechanisms linking GBA1 to PD.

Purpose of the Study:

• To identify shared transcriptomic alterations between GD and PD to uncover molecular modifiers and mechanisms.
• To assess causal relationships between identified genes and PD risk using Mendelian randomization.
• To explore the diagnostic relevance and metabolic implications of these findings in PD.

Main Methods:

• Integrated eighteen transcriptomic datasets from GD, GBA1-associated PD, and sporadic PD cohorts.
• Identified shared, directionally concordant differentially expressed genes (DEGs) and performed pathway enrichment analysis.
• Utilized two-sample Mendelian randomization, machine learning for diagnostic evaluation, and neuron-specific metabolic modeling.

Main Results:

• Shared DEGs were enriched in lysosomal, lipid, redox, and endocrine pathways.
• Mendelian randomization identified several risk and protective genes, including GPNMB, MMP9, TRIM22, and AGT.
• Metabolic modeling revealed convergent but subtype-specific metabolic perturbations, with diagnostic signals concentrated in specific genes.

Conclusions:

• Two mechanistic routes to PD risk are supported: a GBA1-sensitized lysosomal-lipid/redox axis and a GBA1-independent neuronal-endocrine axis.
• These findings explain variable PD risk in GBA1 carriers and highlight potential biomarkers.
• Identified pathways offer targets for stratified therapeutic interventions in Parkinson's disease.