Human cyclophilin 40 unravels neurotoxic amyloids

• DOI: 10.1371/journal.pbio.2001336
• Publication Date: 2017-06-27T17:34:03Z
• Authors: Jeremy D. Baker; Lindsey B. Shelton; Dali Zheng; Filippo Favretto; Bryce A. Nordhues; April Darling; Leia E. Sullivan; Zheying Sun; Parth K. Solanki; Mackenzie D. Martin; Amirthaa Sunthara...; Jonathan J. Sabbagh; Stefan Becker; Eckhard Mandelkow; Vladimir N. Uversky; Markus Zweckstetter; Chad A. Dickey; John Koren; Laura J. Blair
• Keywords: Amyloid (mycology); Intrinsically Disordered Proteins; Tau protein

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