Development of tau phosphorylation-targeting therapies for the treatment of neurodegenerative diseases
Jingfen Su,
Yue Xiao,
Xiaochuan Wang,
Jie Zheng,
Jian-Zhi Wang
Affiliations
Jingfen Su
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Yue Xiao
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430030, China
Xiaochuan Wang
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430030, China
Jie Zheng
Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University; Key Laboratory for Neuroscience (Ministry of Education/National Health Commission), Peking University, Beijing 100083, China; Beijing Life Science Academy, Beijing 102209, China; Corresponding authors.
Jian-Zhi Wang
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China; Corresponding authors.
Hyperphosphorylation of microtubule-associated protein tau is a major driver in the etiology of multiple neurodegenerative diseases, such as Alzheimer’s disease (AD) and other tauopathies. Intracellular accumulation of hyperphosphorylated tau (pTau) decreases microtubule stability, induces protein aggregation, and impairs neuronal plasticity. Increasing attention has been devoted to the development of targeted therapies for modulating tau phosphorylation, including conventional protein kinase inhibitors, phosphatase activators, immunotherapies, as well as a new collection of tau-targeted hetero-bifunctional chimeras such as dephosphorylation-targeting chimeras (DEPTACs), proteolysis targeting chimeras (PROTACs) for pTau, phosphorylation targeting chimeras (phosTACs), and affinity-directed phosphatase (AdPhosphatase) system. In this review, we briefly introduce tau and its role in neurodegenerative diseases, provide progress in the development of pTau targeting therapies, and discuss their advantages and limitations.
