Single-domain Antibody-based Protein Degrader for Synucleinopathies

Overview

Journal Mol Neurodegener

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2024 May 30

PMID 38816762

Authors

Yixiang Jiang

Yan Lin

Amber M Tetlow

Ruimin Pan

Changyi Ji

Xiang-Peng Kong

Erin E Congdon

Einar M Sigurdsson

Affiliations

Soon will be listed here.

Abstract

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-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 α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-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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