{"doi":"10.1101/2024.03.11.584473","title":"Single-Domain Antibody-Based Protein Degrader for Synucleinopathies","abstract":"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 CRBN , 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486816,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":179232,"name":"Yan Lin","orcid":null,"position":1,"is_corresponding":false},{"id":912943,"name":"Amber M. Tetlow","orcid":null,"position":2,"is_corresponding":false},{"id":1038099,"name":"Ruimin Pan","orcid":"0000-0002-6947-1658","position":3,"is_corresponding":false},{"id":374060,"name":"Changyi Ji","orcid":"0000-0002-0846-7954","position":4,"is_corresponding":false},{"id":228625,"name":"Xiang‐Peng Kong","orcid":"0000-0001-5773-2681","position":5,"is_corresponding":false},{"id":367656,"name":"Erin E. Congdon","orcid":"0000-0001-8322-6176","position":6,"is_corresponding":false},{"id":291810,"name":"Einar M. Sigurdsson","orcid":"0000-0003-1451-0952","position":7,"is_corresponding":false},{"id":1240248,"name":"Yixiang Jiang","orcid":"0009-0008-3218-3071","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T02:08:01.404471Z","pmid":"38558982","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}