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A new tau dephosphorylation-targeting chimera for the treatment of tauopathies

Acta Pharmacologica Sinica (2024)Cite this article

A Correction to this article was published on 16 September 2024

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Abstract

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer’s disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

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Fig. 1: D14 is assembled with optimized constitutes.
Fig. 2: D14 simultaneously interacts with tau and PP2A.
Fig. 3: D14 shows limited cytotoxicity in cultured hippocampal neurons.
Fig. 4: D14 decreases tau phosphorylation and morphological atrophy in K18 tau seeds-treated neurons.
Fig. 5: D14 reduces the levels of phosphorylated and total tau in Tau368 mice.
Fig. 6: Repeated D14 administration through the tail vein ameliorates tau-related pathology and improves cognitive function in Tau368 transgenic mice.

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References

  1. Zhang Y, Wu KM, Yang L, Dong Q, Yu JT. Tauopathies: new perspectives and challenges. Mol Neurodegener. 2022;17:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2018;14:399–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li C, Götz J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov. 2017;16:863–83.

    Article  CAS  PubMed  Google Scholar 

  4. Hua L, Zhang Q, Zhu X, Wang RN, You QD, Wang L. Beyond proteolysis-targeting chimeric molecules: designing heterobifunctional molecules based on functional effectors. J Med Chem. 2022;65:8091–112.

    Article  CAS  PubMed  Google Scholar 

  5. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181–200.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Alabi SB, Crews CM. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J Biol Chem. 2021;296:100647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zheng J, Tian N, Liu F, Zhang YD, Su JF, Gao Y, et al. A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies. Signal Transduct Target Ther. 2021;6:269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Su J, Xiao Y, Wei LY, Lei HY, Sun F, Wang WX, et al. Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer’s disease and related tauopathies. Sci Bull (Beijing). 2024;69:1137–52.

    Article  CAS  PubMed  Google Scholar 

  9. Li K, Crews CM. PROTACs: past, present and future. Chem Soc Rev. 2022;51:5214–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goracci L, Desantis J, Valeri A, Castellani B, Eleuteri M, Cruciani G. Understanding the metabolism of proteolysis targeting chimeras (PROTACs): the next step toward pharmaceutical applications. J Med Chem. 2020;63:11615–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figueroa S, Ko E, et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew Chem Int Ed Engl. 2016;55:807–10.

    Article  CAS  PubMed  Google Scholar 

  12. Minko T. Nanoformulation of BRD4-degrading PROTAC: improving druggability to target the ‘undruggable’ MYC in pancreatic cancer. Trends Pharmacol Sci. 2020;41:684–6.

    CAS  Google Scholar 

  13. Li JJ, Zhang XM, Wang M, Li XJ, Mu HJ, Wang AP, et al. Synthesis of a bi-functional dendrimer-based nanovehicle co-modified with RGDyC and TAT peptides for neovascular targeting and penetration. Int J Pharm. 2016;501:112–23.

    Article  CAS  PubMed  Google Scholar 

  14. Milletti F. Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov Today. 2012;17:850–60.

    Article  CAS  PubMed  Google Scholar 

  15. Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, et al. Molecular interactions among protein phosphatase 2A, tau, and microtubules. J Biol Chem. 1999;274:25490–8.

    Article  CAS  PubMed  Google Scholar 

  16. Chu TT, Gao N, Li QQ, Chen PG, Yang XF, Chen YX, et al. Specific knockdown of endogenous tau protein by peptide-directed ubiquitin-proteasome degradation. Cell Chem Biol. 2016;23:453–61.

    Article  CAS  PubMed  Google Scholar 

  17. Maccioni RB, Rivas CI, Vera JC. Differential interaction of synthetic peptides from the carboxyl-terminal regulatory domain of tubulin with microtubule-associated proteins. EMBO J. 1988;7:1957–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC. Regulation of the phosphorylation state and microtubule-binding activity of tau by protein phosphatase 2A. Neuron. 1996;17:1201–7.

    Article  CAS  PubMed  Google Scholar 

  19. Sontag J-M, Nunbhakdi-Craig V, White CL, Halpain S, Sontag E. The protein phosphatase PP2A/Bα binds to the microtubule-associated proteins tau and MAP2 at a motif also recognized by the kinase fyn. J Biol Chem. 2012;287:14984–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Litersky JM, Johnson GV. Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J Biol Chem. 1992;267:1563–8.

    Article  CAS  PubMed  Google Scholar 

  21. Ukmar-Godec T, Fang P, Ibáñez De Opakua A, Henneberg F, Godec A, Pan KT, et al. Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution. Sci Adv. 2020;6:eaba3916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rametti A, Esclaire F, Yardin C, Terro F. Linking alterations in tau phosphorylation and cleavage during neuronal apoptosis. J Biol Chem. 2004;279:54518–28.

    Article  CAS  PubMed  Google Scholar 

  23. Uppalapati M, Lee DJ, Mandal K, Li HY, Miranda LP, Lowitz J, et al. A potent D -protein antagonist of VEGF-A is nonimmunogenic, metabolically stable, and longer-circulating in vivo. ACS Chem Biol. 2016;11:1058–65.

    Article  CAS  PubMed  Google Scholar 

  24. Fawell S, Seery J, Daikh Y, Moore C, Chen LL, Pepinsky B, et al. Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci USA. 1994;91:664–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Green M, Loewenstein PM. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Dis Markers. 1990;8:34–5.

    Google Scholar 

  26. Ishihara H, Martin BL, Brautigan DL, Karaki H, Ozaki H, Kato Y, et al. Calyculin A and okadaic acid: inhibitors of protein phosphatase activity. Biochem Biophys Res Commun. 1989;159:871–7.

    Article  CAS  PubMed  Google Scholar 

  27. Sandal P, Jong CJ, Merrill RA, Song JN, Strack S. Protein phosphatase 2A - structure, function and role in neurodevelopmental disorders. J Cell Sci. 2021;134:jcs248187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang Z, Song M, Liu X, Kang SS, Kwon Il-Sun, Duong DM, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Y, Yang R, Gu J, Yin XM, Jin N, Xie ST, et al. Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging. 2015;36:188–200.

    Article  PubMed  Google Scholar 

  30. Dehmelt L, Halpain S. The MAP2/Tau family of microtubule-associated proteins. Genome Biol. 2005;6:204.

    Article  PubMed  Google Scholar 

  31. You MD, Dong J, Fu YY, Cong ZZ, Fu H, Wei LL, et al. Exposure to Di-(2-ethylhexyl) phthalate during perinatal period gender-specifically impairs the dendritic growth of pyramidal neurons in rat offspring. Front Neurosci. 2018;12:444.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zajkowski T, Nieznanska H, Nieznanski K. Stabilization of microtubular cytoskeleton protects neurons from toxicity of N-terminal fragment of cytosolic prion protein. Biochim Biophys Acta. 2015;1853:2228–39.

    Article  CAS  PubMed  Google Scholar 

  33. Gao Y, Wang YY, Lei HY, Xu ZD, Li SH, Yu HT, et al. A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau. Transl Neurodegener. 2023;12:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Han K, Jeon MJ, Kim SH, Ki D, Bahn JH, Lee KS, et al. Efficient intracellular delivery of an exogenous protein GFP with genetically fused basic oligopeptides. Mol Cells. 2001;12:267–71.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was financially supported by the National Natural Science Foundation of China (No. 82230041, 91949205), Sanming Project of Medicine in Shenzhen (No. SZSM202211010), Guangdong Provincial Key S&T Program (No. 2018B030336001), Peking University Talent Startup Fund (No. BMU2022YJ003) supported by the “Fundamental Research Funds for the Central Universities”, Scientific Project of Beijing Life Science Academy (No. 2024300CC0020). Finally, we thank Prof. Yan Zhou from Wuhan University for the help in the MST method, Prof. Jinwang Ye from Shenzhen University for the generous gifts of K18 proteins, and all members of Wang-lab for helpful discussion and suggestions.

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Author notes

  1. These authors contributed equally: Jing-fen Su, Yue Xiao

Authors and Affiliations

  1. 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

    Jing-fen Su, Yue Xiao, Lin-yu Wei, Hui-yang Lei, Fei Sun, Wei-xia Wang, Xiao-chuan Wang & Jian-zhi Wang

  2. School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yue Xiao & Xiao-chuan Wang

  3. Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China

    Lin-yu Wei

  4. Department of Anesthesiology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    Shi-hong Li

  5. 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

    Jie Zheng

  6. Beijing Life Science Academy, Beijing, 102209, China

    Jie Zheng

  7. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226000, China

    Jian-zhi Wang

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Contributions

JZW and JZ conceptualized and designed the research study. JZW, JZ and XCW supervised the research study. JFS, YX, LYW, HYL, FS, WXW, and SHL conceived and carried out the experiments. JFS and YX carried out animal experiments. JFS and YX analyzed the data. JFS, JZW and JZ wrote and/or reviewed the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiao-chuan Wang, Jie Zheng or Jian-zhi Wang.

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The authors declare no competing interests.

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The original online version of this article was revised: Figure 2f has been corrected.

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Su, Jf., Xiao, Y., Wei, Ly. et al. A new tau dephosphorylation-targeting chimera for the treatment of tauopathies. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01326-4

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