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  Human cyclophilin 40 unravels neurotoxic amyloids.

Baker, J. D., Shelton, L. B., Zheng, D. L., Favretto, F., Nordhues, B. A., Darling, A., et al. (2017). Human cyclophilin 40 unravels neurotoxic amyloids. PLoS Biology, 15(6): e2001336. doi:10.1371/journal.pbio.2001336.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-9E36-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-08DD-E
Genre: Journal Article

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Baker, J. D., Author
Shelton, L. B., Author
Zheng, D. L., Author
Favretto, F., Author
Nordhues, B. A., Author
Darling, A., Author
Sullivan, L. E., Author
Sun, Z. Y., Author
Solanki, P. K., Author
Martin, M. D., Author
Suntharalingam, A., Author
Sabbagh, J. J., Author
Becker, S.1, Author              
Mandelkow, E., Author
Uversky, V. N., Author
Zweckstetter, M.2, Author              
Dickey, C. A., Author
Koren, J., Author
Blair, L. J., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids.

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Language(s): eng - English
 Dates: 2017-06-27
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1371/journal.pbio.2001336
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Title: PLoS Biology
Source Genre: Journal
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Pages: 22 Volume / Issue: 15 (6) Sequence Number: e2001336 Start / End Page: - Identifier: -