Single-Domain Antibody-Based Protein Degrader for Synucleinopathies
Yixiang Jiang1, Yan Lin1, Amber M Tetlow1
1Department of Neuroscience and Physiology, Neuroscience Institute, New York University Grossman School of Medicine, 435 East 30 Street, New York NY 10016, USA.
Biorxiv : the Preprint Server for Biology
|April 1, 2024
Summary
Researchers developed a novel single-domain antibody (sdAb) protein degrader to clear alpha-synuclein (α-syn) buildup in the brain. This innovative therapeutic approach shows promise for treating synucleinopathies by enhancing protein degradation.
Area of Science:
- Neuroscience
- Molecular Biology
- Drug Discovery
Background:
- Synucleinopathies are neurodegenerative disorders marked by alpha-synuclein (α-syn) aggregation in the brain.
- Current treatments for synucleinopathies primarily manage symptoms, lacking a cure.
- The accumulation of α-syn leads to debilitating motor and neuropsychiatric symptoms.
Approach:
- Developed a single-domain antibody (sdAb)-based protein degrader targeting α-syn.
- Engineered the sdAb to also bind Cereblon (CRBN), recruiting the E3 ubiquitin ligase CRL4CRBN.
- This mechanism induces α-syn ubiquitination and subsequent proteasomal degradation.
Key Points:
- The sdAb protein degrader enhances the proteasomal degradation of α-syn.
- This approach complements the natural lysosomal degradation pathways.
- Successful clearance of α-syn was observed in primary cell cultures and mouse models of synucleinopathy.
Conclusions:
- The developed sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies.
- Enhanced brain penetration of sdAbs compared to whole antibodies could improve therapeutic efficacy.
- This strategy offers a novel pathway for treating α-syn aggregation-related neurodegenerative diseases.
