Biology subjects

Kwon, Y. T.

Publications and source records attributed to Kwon, Y. T..

4 recordsLinked to original sources

bioRxiv2025

Targeted degradation of pathologic tau aggregates via AUTOTAC ameliorates tauopathy

The pathogenesis of tauopathies including Alzheimers disease (AD) and progressive supranuclear palsy (PSP) involves the misfolding and aggregation of tau. Here, we employed AUTOTAC to induce the lysosomal degradation of intraneuronal tau aggregates. ATB2005A is a 734-Da chimera that simultaneously binds {beta}-sheet-rich tau aggregates and the autophagic receptor p62/SQSTM1, leading to autophagosomal sequestration and lysosomal co-degradation. In mouse models of tauopathies, orally administered ATB2005A lowered intraneuronal tau aggregates and exerted the therapeutic efficacy in neuroinflammation as well as cognition, behavior, and muscle movements. A Phase 2 clinical trial (U34401-4/2023/14) with companion dogs carrying canine cognitive dysfunction (CCD) demonstrated the efficacy of ATB2005A, as a veterinary medicine, to reverse the disease progression. ATB2005A is under Phase 1 clinical trial with human participants in Korea (202300697). These results validate AUTOTAC as a versatile platform for developing therapeutics to eradicate toxic protein aggregates in a wide range of proteinopathies.

neuroscience↗

bioRxiv2025

Targeted degradation of pathogenic TDP-43 proteins in amyotrophic lateral sclerosis using the AUTOTAC platform

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons and the cytoplasmic aggregation of misfolded proteins in the spinal cord, including TAR DNA-binding protein-43 (TDP-43). More than 97% of ALS cases exhibit pathological TDP-43 inclusions, yet therapeutic strategies that can selectively eliminate these aggregates remain yet to be developed. Here, we employed the AUTOTAC (Autophagy-Targeting Chimera) to degrade TDP-43 aggregates via macroautophagy mediated by the N-recognin p62/SQSTM1 of the N-degron pathway. The AUTOTAC degraders ATC141 and ATC142 were designed to bind and link the oligomeric species of misfolded TDP-43 to p62, which induces the targeting of TDP-43 cargoes to phagophores for lysosomal co-degradation, while sparing monomeric TDP-43. ATC142 induced the degradation of pathological TDP-43 A315T species and its cleaved variant, TDP-25, with DC50 values of 1.25-9.6 nM. In ALS model mice expressing TDP-43 A315T in the spinal cord, oral administration of 10 mg/kg ATC141 with 24 doses reduced TDP-43 aggregates as well as GFAP+ astrocytes and Iba1+ microglia. ATC141 also exerted disease-modifying efficacy to reverse the disease progression in neuromuscular coordination and cognitive function. This oral drug is under Phase 1 clinical trials in South Korea with 76 healthy volunteers aiming to treat ALS, Alzheimers diseases (AD), and progressive supranuclear palsy (PSP). We suggest that AUTOTAC provides a novel strategy to treat a broad range of neurodegenerative diseases. TeaserAUTOTAC degraders induce lysosomal degradation of pathogenic TDP-43 aggregates in a mouse model of amyotrophic lateral sclerosis.

neuroscience↗

bioRxiv2025

Targeted degradation of SARS-CoV-2 via the autophagy-lysosome system using chemical mimetics of the N-degron pathway

In the N-degron pathway, ATE1 transfers the amino acid L-arginine (L-Arg) from Arg-tRNAArg to N-terminal (Nt) residues of cellular proteins. The resulting Arg/N-degrons bind the autophagic receptor p62/SQSTSM-1/Sequestosome-1 to induce lysosomal degradation of various biomaterials. Here, we demonstrate that the chemical mimetics of Arg/N-degrons, termed autophagy-targeting ligands (ATLs), can induce lysosomal degradation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) via p62-mediated macroautophagy. In Vero E6 cells infected with SARS-CoV-2, ATLs promoted p62 self-polymerization and enhanced LC3 synthesis and lipidation, leading to viral sequestration within autophagosomes for lysosomal degradation. In transgenic mice overexpressing human angiotensin-converting enzyme 2 (ACE2), oral administration of ATL1014 inhibited viral replication and increased viability. In a Syrian hamster model, ATL1014 attenuated viral replication in the lungs and demonstrated efficacy in inflammatory lesions and pulmonary congestions. These results identify the N-degron pathway as a potential target for a host-targeting strategy (HTS) against a broad spectrum of viruses.

microbiology↗

bioRxiv2022

ECPAS/Ecm29-Mediated 26S Proteasome Disassembly Is an Adaptive Response to Glucose Starvation

The 26S proteasome consists of loosely associated 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in eukaryotic cells exist as free 20S complexes; however, our mechanistic and physiological understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation in mammalian cells results in the uncoupling of 26S holoenzymes into intact 20S and 19S subcomplexes. Subcomplex affinity-purification and quantitative mass spectrometry revealed that Ecm29 proteasome adaptor and scaffold (ECPAS) is a crucial mediator of this structural remodeling. The loss of ECPAS abrogated 26S dissociation, leading to decreased degradation of 20S proteasome substrates such as puromycylated polypeptides and lysine-less cyclin B. In silico modeling analysis suggested that the conformational changes of ECPAS may commence the disassembly process. ECPAS was also essential for proper endoplasmic reticulum stress response and cell survival during glucose starvation. In addition, we evaluated the role of ECPAS in vivo using the mouse xenograft model and observed that glucose-deprived tumor tissues had significantly elevated 20S proteasome levels. Collectively, our results indicate that the 20S-19S disassembly mediated by ECPAS is a novel mechanism adapting global proteolysis to physiological needs and an effective cellular strategy against proteotoxic stress.

biochemistry↗