Kim, S. T. | bioRxiv Science

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↗

bioRxiv2022

A Phytophthora nucleolar effector, Pi23226, targets to host ribosome biogenesis for necrotrophic cell death

Pathogen effectors target diverse subcellular organelles to manipulate the plant immune system. Although nucleolus has been emerged as a stress marker, and several effectors are localized in the nucleolus, the roles of nucleolar-targeted effectors remain elusive. In this study, we showed Phytophthora infestans infection of Nicotiana benthamiana results in nucleolar inflation during the transition from biotrophic to necrotrophic phase. Multiple P. infestans effectors were localized in the nucleolus: Pi23226 induced cell death in Nicotiana benthamiana and nucleolar inflation similar to that observed in the necrotrophic stage of infection, whereas its homolog Pi23015 and a deletion mutant (Pi23226{Delta}C) did not induce cell death or affect nucleolar size. RNA immunoprecipitation and iCLIP-seq analysis indicated that Pi23226 bound to the 3'-end of 25S rRNA precursors, resulting in the accumulation of unprocessed 27S pre-rRNAs. The nucleolar stress marker NAC082 was strongly upregulated under Pi23226-expressing conditions. Pi23226 subsequently inhibited global protein translation in host cells by interacting with ribosomes. Pi23226 enhanced P. infestans pathogenicity, indicating that Pi23226-induced ribosome malfunction and cell death was beneficial for pathogenesis in the host. Our results provide evidence for the molecular mechanism underlying RNA-binding effector activity in host ribosome biogenesis, and lead to new insights into the nucleolar action of effectors in pathogenesis.

plant biology↗