Subramanian, Manivannan Hyeon, Seung Jae Das, Tanuza Suh, Yoon Seok Kim, Yun Kyung Lee, Jeong-Soo Song, Eun Joo Ryu, Hoon Yu, Kweon 2024-01-19T14:32:07Z 2024-01-19T14:32:07Z 2022-01-10 2021-06 2041-1723 https://pubs.kist.re.kr/handle/201004/116898 The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer's disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD. Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer's disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration. English Nature Publishing Group UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation Article 10.1038/s41467-021-23597-9 1 Nature Communications, v.12, no.1 Nature Communications 12 1 Y scie scopus 000660869100001 2-s2.0-85107135290 Multidisciplinary Sciences Science & Technology - Other Topics Article HUMAN NEURONAL TAUOPATHIES ALZHEIMERS-DISEASE WILD-TYPE NEURODEGENERATION RECOGNITION CLEARANCE PHOSPHORYLATION AGGREGATION APOPTOSIS MODEL UBE4B autophagy Tau