Chaperoning activity of the cyclophilin family prevents tau aggregation

Abstract

Tauopathies, such as Alzheimer's disease, are characterized by the misfolding and progressive accumulation of the microtubule associated protein tau. Chaperones, tasked with maintaining protein homeostasis, can become imbalanced with age and contribute to the progression of neurodegenerative disease. Cyclophilins are a promising pool of underinvestigated chaperones with peptidyl‐prolyl isomerase activity that may play protective roles in regulating tau aggregation. Using a Thioflavin T fluorescence‐based assay to monitor in vitro tau aggregation, all eight cyclophilins, which include PPIA to PPIH prevent tau aggregation, with PPIB, PPIC, PPID, and PPIH showing the greatest inhibition. The low thermal stability of PPID and the strong heparin binding of PPIB undermines the simplistic interpretation of reduced tau aggregation. In a cellular model of tau accumulation, all cyclophilins, except PPID and PPIH, reduce insoluble tau. PPIB, PPIC, PPIE, and PPIF also reduce soluble tau levels with PPIC exclusively protecting cells from tau seeding. Overall, this study demonstrates cyclophilins prevent tau fibril formation and many reduce cellular insoluble tau accumulation with PPIC having the greatest potential as a molecular tool to mitigate tau seeding and accumulation.

Stress biology: Complexity and multifariousness in health and disease

“…Laura Blair (University of South Florida, USA) presented her group’s findings identifying new molecular chaperone regulators of tau seeding, including multiple J-domain proteins (JDPs, also called Hsp40/DnaJ proteins), cochaperones of Hsp70, and cyclophilin C (PPIC). 86 , 87 Aberrant Tau accumulation is associated with neurodegeneration in Alzheimer’s disease and other tauopathies. Of particular interest, DnaJB6b was found to reduce tau levels and interact with tau complexes.…”

A novel role for the peptidyl-prolylcis-transisomerase Cyclophilin A in DNA-repair following replication fork stalling via the MRE11-RAD50-NBS1 complex

“…Other classes of PPIs, such as the well-known Parvulin family member PIN1 and certain FKBPs (FK506-binding proteins), directly influence DNA repair and the DNA damage response [17][18][19][20]. CYPA's PPI function is implicated in supervising optimal protein folding, in regulating local structural transitions influencing protein function by essentially acting as a molecular rheostat, and as a 'holdase' in controlling liquid-liquid phase separation (LLPS) of certain intrinsically disordered proteins (IDPs) and proteins with defined regions of disorder [21][22][23][24][25][26][27][28][29][30][31][32].…”