UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation

Manivannan Subramanian, Seung Jae Hyeon, Tanuza Das, Yoon Seok Suh, Yun Kyung Kim, Jeong-Soo Lee, Eun Joo Song (), Hoon Ryu () and Kweon Yu ()
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Manivannan Subramanian: Metabolism and Neurophysiology Research Group, KRIBB
Seung Jae Hyeon: Center for Neuroscience, Brain Science Institute, KIST
Tanuza Das: Biomedical Research Institute, KIST
Yoon Seok Suh: Metabolism and Neurophysiology Research Group, KRIBB
Yun Kyung Kim: Convergence Research Center of Dementia, KIST
Jeong-Soo Lee: Metabolism and Neurophysiology Research Group, KRIBB
Eun Joo Song: Ewha Womans University
Hoon Ryu: Center for Neuroscience, Brain Science Institute, KIST
Kweon Yu: Metabolism and Neurophysiology Research Group, KRIBB

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23597-9

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