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Cell Stress and Chaperones

, Volume 15, Issue 4, pp 415–421 | Cite as

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

  • Han Cheng
  • Lei Wang
  • Chih-chen Wang
Original Paper

Abstract

α-Synuclein (αSyn) is the main component of Lewy bodies formed in midbrain dopaminergic neurons which is a pathological characteristic of Parkinson's disease. It has been recently showed to induce endoplasmic reticulum (ER) stress and impair ER functions. However, the mechanism of how ER responds to αSyn toxicity is poorly understood. In the present study, we found that protein disulfide isomerase (PDI), a stress protein abundant in ER, effectively inhibits αSyn fibril formation in vitro. In PDI molecule with a structure of abb’xa’c, domain a’ was found to be essential and sufficient for PDI to inhibit αSyn fibril formation. PDI was further found to be more avid for binding with intermediate species formed during αSyn fibril formation, and the binding was more intensive in the later lag phase. Our results provide new insight into the role of PDI in protecting ER from the deleterious effects of misfolded protein accumulation in many neurodegenerative diseases.

Keywords

Protein disulfide isomerase α-Synuclein Fibril Isothermal titration calorimetry 

Notes

Acknowledgements

This work was supported by grants from Chinese Ministry of Science and Technology (2006CB806508 and 2006CB910903) and Chinese Academy of Sciences (KSCX2-YW-R-119). We sincerely thank Prof. Hongyu Hu for his generous gift of the plasmid of pET-3a containing human αSyn cDNA and Prof. Sarah Perrett of this Institute for her kind gift of Ure2p protein. Prof. Yigong Shi in Tsinghua University and Prof. Yi Liang in Wuhan University are appreciated for their kind help on ITC experiments.

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Copyright information

© Cell Stress Society International 2009

Authors and Affiliations

  1. 1.National Laboratory of Biomacromolecules, Institute of BiophysicsChinese Academy of SciencesBeijingChina
  2. 2.Graduate School of the Chinese Academy of SciencesBeijingChina

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