Human cyclophilin 40 unravels neurotoxic amyloids

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. Author summaryInside the cell, proteins need to be folded to be functional and active. Molecular chaperones are key enzymes that assist in folding proteins by stabilizing nascent polypeptide chains and by facilitating interactions that help stabilize a final structure. These PLOS Biology | https://doi.org/10.1371/journal.pbio

The molecular language of membraneless organelles

“…Indeed, peptidyl-prolyl cis-trans isomerases colocalize with stress granules, bind hydrogels formed from the PrLDs of RBPs, and increase the solvent accessibility of certain residues in hnRNPA2 as it assembles into fibrils (129). Importantly, peptidyl-prolyl cis-trans isomerases can also function as protein disaggregases with activity against amyloid fibrils (87,156). Thus, proline cis-trans isomerization may be another mechanism by which cells modulate the phase behavior of proteins.…”

Structure, Function, and Regulation of the Hsp90 Machinery

“…Importantly, Aha1 overexpression also led to enhanced tau aggregation in a transgenic mouse model and in vitro, chemical disruption of the Aha1:Hsp90 complex could reverse the Aha1-mediated effect (Shelton et al 2017a). In contrast, PP5 is known to dephosphorylate tau and restore the microtubulebinding ability and the PPIase Cyp40 prevented tau-induced toxicity in vivo (Gong et al 2004;Baker et al 2017). Additionally, depletion of Hop or CHIP entailed accumulation of tau proteins, indicating that these chaperones are necessary for tau clearance (Dickey et al 2008;Jinwal et al 2013).…”

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

“…Another class of heat shock proteins exist in bacterial, fungal and plant systems, i.e., the Hsp110 AAA + ATPase disaggregases that can disassemble amyloid and protein aggregates (Torrente and Shorter, 2013). Recent studies indicate that proteins with disaggregase function (some with Hsp homology) exist in the animal kingdom but their role appears to be unclear (Baker et al, 2017;Taguchi et al, 2019;Avellaneda et al, 2020). In this context, it is notable that physiologic or reversible protein aggregates are observed in yeast as a reserve pool of proteins to respond to stress (Saad et al, 2017).…”