ARRDC4 drives Tau pathology via USP14‐mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease
Jiaqi Liu, Bing‐Wen Xiao, Xiaohan Mai, Yi‐Chun Wang, Yiyan Fei, Yang Wang, Steven X. HouAbstract
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.