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bioRxiv · 10.1101/2024.03.11.584473

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies

Jiang, Y.·Lin, Y.·Tetlow, A. M.·Pan, R.·Ji, C.·Kong, X.-P.·Congdon, E. E.·Sigurdsson, E. M.
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Abstract

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of -synuclein (-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of -syn. This sdAb derivative targets both -syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces -syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of -syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of -syn, we improved clearance of -syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

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Jiang, Y., Lin, Y., Tetlow, A. M., Pan, R., Ji, C., Kong, X.-P., Congdon, E. E., Sigurdsson, E. M.. 2024-03-13. Single-Domain Antibody-Based Protein Degrader for Synucleinopathies. https://doi.org/10.1101/2024.03.11.584473

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