2. Academic Validation
  3. Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality

Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality

  • J Am Chem Soc. 2023 Feb 8. doi: 10.1021/jacs.2c11706.
Zhenyi Hu 1,  Po-Han Chen 1 2 3,  Wenxue Li 4,  Todd Douglas 1,  John Hines 1,  Yansheng Liu 4,  Craig M Crews 1 5 6 7
Affiliations

Affiliations

  • 1 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States.
  • 2 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan.
  • 3 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan city 701, Taiwan.
  • 4 Yale Cancer Biology Institute, West Haven, Connecticut 06516, United States.
  • 5 Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
  • 6 Department of Pharmacology, Yale University, New Haven, Connecticut 06511, United States.
  • 7 Yale University School of Medicine, New Haven, Connecticut 06511, United States.
PMID: 36753634 DOI: 10.1021/jacs.2c11706
Abstract

Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated protein tau plays an important pathological role in the development of Alzheimer's disease and Other tauopathies. In vivo studies using kinase inhibitors suggest that reducing tau phosphorylation levels has therapeutic potential; however, such approaches showed limited benefits. We sought to further develop our phosphorylation targeting chimera (PhosTAC) technology to specifically induce tau dephosphorylation. Herein, we use small molecule-based PhosTACs to recruit tau to PP2A, a native tau Phosphatase. PhosTACs induced the formation of a stable ternary complex, leading to rapid, efficient, and sustained tau dephosphorylation, which also correlated with the enhanced downregulation of Tau Protein. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. We believe that PhosTAC possesses several advantages over current strategies to modulate tau phosphorylation and represents a new avenue for disease-modifying therapies for tauopathies.

Figures
Products