Deep next-generation proteomics and network analysis reveal systemic and tissue-specific patterns in Fabry disease

Area of Science:

• Biochemistry
• Genetics
• Systems Biology

Background:

• Fabry disease (FD) is an X-linked lysosomal disorder caused by alpha-galactosidase A deficiency.
• Glycosphingolipid accumulation in FD affects kidneys, heart, and CNS, leading to reduced life expectancy.
• Secondary cellular and tissue dysfunctions contribute to the FD clinical phenotype.

Purpose of the Study:

• To perform large-scale deep plasma targeted proteomic profiling in Fabry disease patients.
• To identify proteomic signatures and understand molecular mechanisms in FD pathogenesis.
• To explore the connection between tissue metabolic remodeling and plasma proteomics in FD.

Main Methods:

• Analyzed plasma protein profiles of 55 FD patients and 30 controls using next-generation plasma proteomics (1463 proteins).
• Applied systems biology and machine learning approaches for data analysis.
• Utilized network strategies to investigate patient-specific tissue metabolic remodeling.

Main Results:

• Identified 615 differentially expressed proteins (476 upregulated, 139 downregulated) separating FD patients from controls.
• Observed functional remodeling in cytokine-mediated pathways, extracellular matrix, and lysosomal proteome.
• Described a 17-protein predictive signature (e.g., CD200, SPINT1, FGFR2) for FD.

Conclusions:

• Pro-inflammatory cytokines and extracellular matrix remodeling are implicated in FD pathogenesis.
• Plasma proteomics reveals a link to tissue-wide metabolic remodeling in FD.
• Findings support further research for improved FD diagnostics and therapeutics.