{"messages":[{"status":"ok","category":"all"}], "collection":[{"title":"Single-Domain Antibody-Based Autophagosome-Targeting Chimera for Tau Clearance and Motor Function Restoration in Tauopathies","authors":"Sigurdsson, E.; Jiang, Y.; Tetlow, A. M.; Lin, Y.; Ji, C.; Laborc, K. F.; Mar, A. C.; Pan, R.; Kong, X.-P.; Congdon, E. E.","author_corresponding":"Einar Sigurdsson","author_corresponding_institution":"New York University Grossman School of Medicine","doi":"10.1101\/2025.06.30.662446","date":"2025-07-04","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/04\/2025.06.30.662446.source.xml","abstract":"Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge. Here, we present 1D9-LIR{Delta}TP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance via the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIR{Delta}TP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In frontotemporal dementia (FTD) patient-derived neurons and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIR{Delta}TP53INP2 significantly reduced tau levels and improved motor function in mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.","published":"NA","server":"bioRxiv"}]}