ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.
- 1State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Cell and Developmental Biology at School of Life Sciences, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, China.
- 2Shanghai Engineering Research Center of Ultra-precision Optical Manufacturing, College of Future Information Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai, China.
Abstract
Introduction
Hyperphosphorylated Tau accumulation drives neurodegeneration in Alzheimer's disease (AD), but mechanisms linking impaired Tau ubiquitination to disease progression remain incompletely defined.Methods
We integrated Drosophila RNAi screening, human AD datasets, cellular assays, and mouse tauopathy models to evaluate arrestin domain-containing 4 (ARRDC4) in Tau pathology. ARRDC4-dependent regulation of Tau ubiquitination was examined using proteomics, proximity labeling, co-immunoprecipitation, BiFC, domain mapping, genetic suppression, and small-molecule interference.Results
ARRDC4 was upregulated in AD-relevant human and animal datasets and correlated with Tau burden. ARRDC4 overexpression promoted Tau phosphorylation, self-association, seeded aggregation, secretion, and inflammatory activation. Mechanistically, ARRDC4 brought Tau and USP14 into proximity, suppressing Tau ubiquitination. Genetic ARRDC4 deficiency or pharmacological disruption of the ARRDC4-USP14 interface restored Tau ubiquitination and ameliorated Tau pathology, neuroinflammation, neuronal injury, and behavioral deficits across cellular, Drosophila, and mouse models.Discussion
ARRDC4 is a regulator of Tau proteostasis and a potential therapeutic target for Tau-associated AD pathology.
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BibTeX
@article{liu2026arrdc4,
title = {{ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.}},
author = {Jiaqi Liu and Bing-Wen Xiao and Xiaohan Mai and Yi-Chun Wang and Yiyan Fei and Yang Wang and Steven X Hou},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2026},
month = oct,
doi = {10.1002/alz.71926},
url = {https://europepmc.org/article/MED/42957973},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.
AU - Jiaqi Liu
AU - Bing-Wen Xiao
AU - Xiaohan Mai
AU - Yi-Chun Wang
AU - Yiyan Fei
AU - Yang Wang
AU - Steven X Hou
PY - 2026
DA - 2026/10/01
JO - Alzheimer's & dementia : the journal of the Alzheimer's Association
DO - 10.1002/alz.71926
UR - https://europepmc.org/article/MED/42957973
AB - Introduction Hyperphosphorylated Tau accumulation drives neurodegeneration in Alzheimer's disease (AD), but mechanisms linking impaired Tau ubiquitination to disease progression remain incompletely defined.Methods We integrated Drosophila RNAi screening, human AD datasets, cellular assays, and mouse tauopathy models to evaluate arrestin domain-containing 4 (ARRDC4) in Tau pathology. ARRDC4-dependent regulation of Tau ubiquitination was examined using proteomics, proximity labeling, co-immunoprecipitation, BiFC, domain mapping, genetic suppression, and small-molecule interference.Results ARRDC4 was upregulated in AD-relevant human and animal datasets and correlated with Tau burden. ARRDC4 overexpression promoted Tau phosphorylation, self-association, seeded aggregation, secretion, and inflammatory activation. Mechanistically, ARRDC4 brought Tau and USP14 into proximity, suppressing Tau ubiquitination. Genetic ARRDC4 deficiency or pharmacological disruption of the ARRDC4-USP14 interface restored Tau ubiquitination and ameliorated Tau pathology, neuroinflammation, neuronal injury, and behavioral deficits across cellular, Drosophila, and mouse models.Discussion ARRDC4 is a regulator of Tau proteostasis and a potential therapeutic target for Tau-associated AD pathology.
SN - 1552-5260
SN - 1552-5279
ER -