Human Cyclophilin 40 Unravels Neurotoxic Amyloids

Authors

Jeremy D. Baker, University of South Florida
Lindsey B. Shelton, University of South Florida
Dali Zheng, University of South Florida
Filippo Favretto, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
Bryce A. Nordhues, University of South Florida
April Darling, University of South Florida
Leia E. Sullivan, University of South Florida
Zheying Sun, University of South Florida
Parth K. Solanki, University of South Florida
Mackenzie D. Martin, University of South Florida
Amirthaa Suntharalingam, University of South Florida
Jonathan J. Sabbagh, University of South Florida
Stefan Becker, Max Planck Institute for Biophysical Chemistry
Eckhard Mandelkow, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Vladimir N. Uversky, University of South FloridaFollow
Markus Zweckstetter, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
Chad A. Dickey, University of South Florida
John Koren III, University of South Florida
Laura J. Blair, University of South FloridaFollow

Document Type

Article

Publication Date

2017

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pbio.2001336

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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

PLoS Biology, v. 15, issue 6, art. e2001336

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Scholar Commons Citation

Baker, Jeremy D.; Shelton, Lindsey B.; Zheng, Dali; Favretto, Filippo; Nordhues, Bryce A.; Darling, April; Sullivan, Leia E.; Sun, Zheying; Solanki, Parth K.; Martin, Mackenzie D.; Suntharalingam, Amirthaa; Sabbagh, Jonathan J.; Becker, Stefan; Mandelkow, Eckhard; Uversky, Vladimir N.; Zweckstetter, Markus; Dickey, Chad A.; III, John Koren; and Blair, Laura J., "Human Cyclophilin 40 Unravels Neurotoxic Amyloids" (2017). Molecular Medicine Faculty Publications. 259.
https://digitalcommons.usf.edu/mme_facpub/259