Fig. 1

Design and working model for a single-domain antibody (sdAb)-based protein degrader targeting synucleinopathies. The degrader molecule is composed of anti-α-syn sdAb 2D8 connected via a variable-size linker to thalidomide, an E3-ligase recruiting ligand that engages with CRL4^CRBN. This degrader molecule can enter the mouse brain after i.v. injection and target α-syn both extracellularly and intracellularly. Specifically, extracellularly, the sdAb may sequester α-syn aggregates and disrupt their assembly, and thereby collectively prevent the spread of α-syn pathology between neurons. Intracellularly, the protein degrader may bind to α-syn aggregates within the endosomal-lysosomal system and facilitate their disassembly, which would result in better access of lysosomal enzymes to degrade the aggregates. The degrader molecule also brings α-syn and E3 ligase into proximity to form a ternary complex, which is predicted to mediate α-syn ubiquitination and trigger its degradation by the proteasome. This working model provides a framework for the development of protein degraders for the treatment of synucleinopathies. Abbreviations: α-syn = α-synuclein, E3 = E3 ligase, E2 = E2 ligase, Ub = ubiquitin