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Abundant neuroprotective chaperone Lipocalin-type prostaglandin D synthase (L-PGDS) disassembles the Amyloid-β fibrils.

Sci Rep. 2019 Aug 29;9(1):12579
Bhuvaneswari Kannaian 1 , Bhargy Sharma 1 , Margaret Phillips 1 , Anup Chowdhury 1 , Malathy S S Manimekalai 1 , Sunil S Adav 2 , Justin T Y Ng 1 , Ambrish Kumar 3 , Sierin Lim 3 , Yuguang Mu 1 , Siu K Sze 1 , Gerhard Grüber 1 , Konstantin Pervushin 4
Bhuvaneswari Kannaian 1 , Bhargy Sharma 1 , Margaret Phillips 1 , Anup Chowdhury 1 , Malathy S S Manimekalai 1 , Sunil S Adav 2 , Justin T Y Ng 1 , Ambrish Kumar 3 , Sierin Lim 3 , Yuguang Mu 1 , Siu K Sze 1 , Gerhard Grüber 1 , Konstantin Pervushin 4
+ et al

[No authors listed]

Author information
  • 1 School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
  • 2 Singapore Phenome Centre, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 636921, Singapore.
  • 3 School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, 637459, Singapore.
  • 4 School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore. kpervushin@ntu.edu.sg.

摘要


Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1-40), abbreviated as Aβ40, and Aβ(25-35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer's disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25-35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model.