David E. Kang (University of South Florida) | 한빛사논문 > 한빛사

한빛사논문

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University of South Florida

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Proc. Natl. Acad. Sci. USA, First published February 18, 2020 | https://doi.org/10.1073/pnas.1917194117 β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates

Jung-A A. Woo^a,b,1, Tian Liu^a,c, Cenxiao C. Fang^a,c, Maria A. Castaño^a, Teresa Kee^a,c, Ksenia Yrigoin^a, Yan Yan^a,c, Sara Cazzaro^a,c, Jenet Matlack^a,c, Xinming Wang^a, Xingyu Zhao^a,c, David E. Kang^a,c,d,1, and Stephen B. Liggett^a,b,e,1

^aUniversity of South Florida Health Byrd Alzheimer’s Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33613; ^bDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33613; ^cDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33613; ^dResearch Division, James A. Haley Veteran’s Administration Hospital, Tampa, FL 33612; and ^eDepartment of Medical Engineering, University of South Florida, Tampa, FL 33613

¹To whom correspondence may be addressed.

Abstract

Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. β-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer’s as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with β-arrestin2−/− mice, show that β-arrestin2 stabilizes pathogenic tau and promotes tau aggregation. Cell and mouse models of FTLD showed this to be maladaptive, fueling a positive feedback cycle of enhanced neuronal tau via non-GPCR mechanisms. Genetic ablation of β-arrestin2 markedly ablates tau pathology and rescues synaptic plasticity defects in tau P301S transgenic mice. Atomic force microscopy and cellular studies revealed that oligomerized, but not monomeric, β-arrestin2 increases tau by inhibiting self-interaction of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized β-arrestin2 with virus encoding β-arrestin2 mutants acting as dominant-negatives markedly reduces tau-laden neurofibrillary tangles in FTLD mice in vivo. Reducing β-arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.

β-arrestin2, tau, tauopathies, Alzheimer’s disease, autophagy

논문정보

형식Research article
게재일2020년 02월 (BRIC 등록일 2020-02-28)
연구진국외 연구진
분야 의약학 > 신경의학

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