Single-vesicle PlAtform for Real-Time detection of membrane-catalyzed Aggregation and transmission

Objetivo

Parkinsons disease (PD) is a neurodegenerative disorder characterized by misfolding and aggregation of the protein alpha-synuclein (αS). Long before clinical symptoms arise small toxic αS oligomers (αSO) are already present and causing cellular membrane damage and seeding aggregation. Mounting evidence indicates that cell membranes not only recruit αS but may actively catalyze aggregation and facilitate transmission between cells. However, direct observation of these early-stage, membrane-seeded events remains technically challenging and hidden in current screening assays.
SPARTA (Single-Vesicle Platform for Real-Time Detection of Membrane-Catalyzed Aggregation and Transmission) reframes the problem by shifting away from protein-centric detection to focusing on the protein triggered membrane response, establishing a sensitive and single-vesicle platform capable of direct observation of αSO interactions with membranes in real-time. The platform will track individual protein aggregates and map the effects on synthetic designed lipid libraries and natural extracellular vesicles and synaptic vesicles. It enables detection of rare but critical events such as membrane leakage, pore formation, protein membrane transmission, and early aggregation which are invisible in conventional bulk assays due to the highly heterogenous nature of both membranes and protein aggregates. Through controlled lipid screening and live-cell imaging, SPARTA will systematically uncover mechanistic insight in how membrane composition influences aggregation and transmission of αSO.
Ultimately, using SPARTA, a miniaturized diagnostic platform will be developed based on arrays of fluorescently barcoded single-vesicle and state-of-the-art microscopy, capable of detecting αSO with minimal material input and time, paving the way for early, non-invasive detection of PD and screening of therapeutic candidates.