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Progress in Chemistry 2022, Vol. 34 Issue (7): 1619-1625 DOI: 10.7536/PC220534 Previous Articles   Next Articles

• Review •

The Mechanism of Protein Condensation in Neurodegenerative Diseases

Muya Zhang, Jiaqi Liu, Wang Chen, Liqiang Wang, Jie Chen, Yi Liang()   

  1. College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University,Wuhan 430072, China
  • Received: Revised: Online: Published:
  • Contact: Yi Liang
  • Supported by:
    National Natural Science Foundation of China(32071212); National Natural Science Foundation of China(31770833); National Natural Science Foundation of China(31570779); China Postdoctoral Science Foundation(2021TQ0252); China Postdoctoral Science Foundation(2021M700103)
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Protein and RNA molecules tend to form supramolecular assemblies called membrane-less organelles via liquid-liquid phase separation of proteins in cells. These organelles have fusion properties similar to liquid droplets formed by biological macromolecules when their concentrations are higher than saturation concentrations. Upon aging, these dynamic droplets change their material properties and transform into gels, followed by formation of solid condensates. It is well known that proteins with low-complexity domains undergo liquid-liquid phase separation. The common pathological feature of neurodegenerative diseases such as transmissible spongiform encephalopathy, amyotrophic lateral sclerosis, and Alzheimer’s disease is toxic oligomers or amyloid aggregates formed by misfolded proteins including prion protein, DNA- and RNA-binding protein TDP-43, and Tau protein. A large number of studies have shown that prion protein, TDP-43, and Tau protein all undergo liquid-liquid phase separation and form protein condensates. This review summarizes the role of protein phase separation and condensation in neurodegenerative diseases, elaborates the mechanism of protein condensation modulating transmissible spongiform encephalopathies, TDP-43 proteinopathies, and tauopathies, and focuses on the initiation effect of phase separation on aggregation and toxicity of misfolded proteins in neurodegenerative diseases. Finally, we discuss and prospect the challenges and opportunities of association study between protein condensation and neurodegenerative diseases.

Contents

1 Introduction

2 Liquid-liquid phase separation and condensation of prion proteins

3 Liquid-liquid phase separation and condensation of TDP-43

4 Liquid-liquid phase separation and condensation of Tau protein

5 Discussion

6 Challenge and outlook

Key words: protein phase separation, neurodegenerative diseases, prion protein, TDP-43, Tau, condensate
Fig. 1 Comparison of the structures of full-length wild-type prion protein (PrP) fibril, the E196K fibril, and the 263K prion fibril
Fig. 2 Liquid-liquid phase separation and liquid-to-solid phase transition of protein and RNA molecules
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