Mapping preclinical neurodegeneration: A window into genetic prion disease progression

Introduction: Exosomes, a distinct subset of extracellular vesicles (EVs), have emerged as a valuable source of biomarkers. Their ability to offer real-time insights into disease progression through liquid biopsies makes them a paradigm-shifting technique for neurodegenerative diseases.

Objectives: By combining state-of-the-art proteomics with ultrasensitive seeding assays, this project seeks to detect disease-associated changes in EV cargoes of neuronal origin. The project focuses on genetic prion disease, specifically individuals affected by Fatal Familial Insomnia (FFI), and compares them with age-matched healthy controls.

Methods: We employed an efficient magnetic nanowire-based methodology to isolate neuronal exosomes from the blood plasma of FFI patients and healthy controls. The isolations were thoroughly characterized and subjected to quantitative proteomic analysis, followed by validations.

Results: Efficient enrichment of EV-fractions was comprehensively validated according to the standards of the International Society for Extracellular Vesicles. The significant candidate hits from quantitative proteomic analysis were verified by ELISA assays in internal and external cohorts. Notably, one of the candidate proteins (SERPINA3) consistently exhibited significantly elevated levels in both symptomatic and asymptomatic carriers of the FFI mutation compared to healthy controls. These results were corroborated across cohorts in Germany, Spain, Italy, and Portugal.

Conclusions: A marked increase in SERPINA3ꟷa serine protease inhibitor and reporter of inflammatory statusꟷin both FFI symptomatic patients and particularly in healthy mutation carriers (asymptomatic) underlines its potential as a minimally invasive biomarker for assessing disease risk and progression.  Ongoing longitudinal studies are expected to yield additional insights into its utility for monitoring disease trajectories.

Funded by: JPND2021