Development of a Targeted BioPROTAC Degrader Selective for Misfolded SOD1

Authors

Christen G Chisholm
Rachael Bartlett
Mikayla L Brown
Emma-Jayne Proctor
Natalie E Farrawell
Jody Gorman
Fabien Delerue
Lars M Ittner
Kara L Vine-Perrow
Heath Ecroyd
Neil R Cashman
Darren N Saunders
Luke McAlary
Jeremy S Lum
Justin J Yerbury

Language

English

Publication Date

11-10-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-65481-w

PMID

41213972

PMCID

PMC12603324

PubMedCentral® Posted Date

11-10-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1G93A mouse model of ALS. Delayed disease progression is associated with protection of motor neurons, a reduction of insoluble SOD1 accumulation and preservation of innervated neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases.

Keywords

Animals, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Mice, Transgenic, Mice, Protein Folding, Humans, Disease Models, Animal, Proteolysis, Motor Neurons, Ubiquitin-Protein Ligases, CRISPR-Cas Systems, Disease Progression, HEK293 Cells, Immunohistochemistry, Ubiquitin ligases, Phenotypic screening

Published Open-Access

yes

Recommended Citation

Chisholm, Christen G; Bartlett, Rachael; Brown, Mikayla L; et al., "Development of a Targeted BioPROTAC Degrader Selective for Misfolded SOD1" (2025). Faculty, Staff and Student Publications. 5535.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5535