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Title: Human cyclophilin 40 unravels neurotoxic amyloids}
Article:
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.
Introduction:
Most mammalian proteins have intrinsic sequences that promote amyloid fibril formation[1]. This is believed to be a natural process to prevent the formation of more toxic amorphous, intermediate structures[1, 2]. However, in some cases such as neurodegenerative disease, aberrant amyloid formation promotes proteotoxicity[3]. Recent evidence suggests endogenous protein complexes have the ability to dissolve these potentially toxic amyloidogenic structures[4]. This work not only has shed light on novel cellular pathways of disaggregation but also suggests that these proteins could be exploited to mitigate disease pathogenesis. For example, the yeast disaggregase heat-shock protein( Hsp) 104 utilizes ATP hydrolysis to disaggregate a variety of human proteins in a yeast model[5, 6]. More recently, the human Hsp70/DnaJ/Hsp110 complex was shown to facilitate the disaggregation of amyloid substrates in vitro in an ATP-dependent manner[7], but the dynamic and ubiquitous nature of aggregation and disaggregation in cells suggests that a more energy-efficient process might exist, one not dependent on ATP. However, a mammalian ATP-independent amyloid unraveling enzyme has yet to be identified. For many proteins, amyloidogenesis is significantly affected by structurally rigid proline residues[8, 9], which unlike other amino acids have a more energetically favorable cis-conformation[10]. This unique nature of proline residues enables major changes in protein tertiary structure through cis-trans isomerization[11]. In neurodegenerative disorders, such as Alzheimer’s disease( AD) and Parkinson’s disease( PD), amyloidogenic proteins( Aβ and tau in AD and α-synuclein in PD) form stacked β-sheets[10–12] containing β-turns[13]. Because proline residues, which are enriched in tau and other intrinsically disordered proteins, are frequently found in β-turns[14], we hypothesized that enzymes capable of twisting these residues could unravel amyloids. The family of cis/trans peptidyl-prolyl isomerases( PPIases) is diverse[15] and, perhaps most importantly, does not require the use of ATP to isomerize proline residues[16]. Previous work, by our group as well as others, demonstrated that PPIases regulate tau aggregation[17–19]. Despite the fact that β-turns often contain prolines, amyloid disaggregation via PPIases has never been demonstrated. Thus, we speculated that discrete PPIases may disaggregate amyloids in a proline-dependent manner. Here, we describe the isomerase-dependent effects of human cyclophilin 40( CyP40) in amyloid disaggregation. CyP40 is a member of the cyclophilin family, which along with FK-506 binding proteins( FKBPs) and parvulins comprise a group of proteins known as immunophilins[15]. Cyclophilins( CyPs) are defined by their ability to bind cyclosporin A( CsA). Upon binding, CyPs suppress the immune system through deactivation of calcineurin, a regulator of inflammation-inducing transcription factors[20]. CyPs also play a key role in the folding of nascent proteins by catalyzing the cis to trans conformation of proline residues, a rate-limiting step in proper folding[21, 22]. Recent work has shown that the isomerase activity of CyP40 is regulated through its interaction with Hsp90 and when CyP40 is bound to Hsp90, isomerase activity is reduced. Cellular stress can release CyP40 from Hsp90, subsequently increasing CyP40 isomerase and chaperone activity[23]. In this study, we identified a novel disaggregation mechanism. For the first time, we showed that a PPIase is capable of disaggregating amyloids. We demonstrated that CyP40 exhibits disaggregation activity dependent on interactions with proline residues and independent of cofactors such as ATP. Further, 2 conformational states of CyP40, found in the Protein Data Bank, provided evidence for a potential mechanism by which amyloid binding and subsequent conformational changes in CyP40 may drive ATP-independent disaggregation activity. Transduction of CyP40 in a tauopathic brain reduced tau oligomers and tangles, yielded significant improvements in neuronal health, and preserved cognitive function. Together, these data implicate CyP40 as a potential therapeutic intervention for tauopathies and other amyloidogenic disorders.
Discussion:
In this study, we describe the disaggregation activity of the human cyclophilin, CyP40. This is the first description of a PPIase disaggregating neurodegenerative amyloids, such as tau and α-syn. This disaggregation is dependent on the PPIase activity of CyP40 and is ATP independent. The distinct structural properties of CyP40 may enable this ATP-independent process to occur and thus may be unique to CyP40 among other PPIases. Disaggregation of tau fibrils by CyP40 reduced pathogenic tau, concomitant with decreased neuronal toxicity and increased cognitive performance. While being the first human PPIase to display disaggregation activity, CyP40 is not the first disaggregase to be identified. Certain chaperone complexes have been shown to facilitate the disaggregation of oligomers and fibrils[4, 38, 40]. For example, the Hsc70/DNAJB1/Apg2 containing complex was shown to reverse the formation of α-syn fibrils in vitro. Identification of this complex was notable because, while previous attempts at chaperone-mediated amyloid disassembly required weeks of incubation in vitro[13], this complex solubilized α-syn fibrils in under an hour[4]. Disaggregation by the Hsc chaperone complex required ATP; however, our study demonstrated that fibrils could be disaggregated with similar kinetics by CyP40 in the absence of ATP. Regardless of energy dependence, the existence of amyloid disaggregases presents a new avenue for therapeutic strategies. The procognitive effects of CyP40 overexpression in the tauopathic brain suggest that strategies to either induce or deliver disaggregases to the central nervous system could halt or even rescue cognitive deficits associated with neurotoxic amyloids. We hypothesize 2 possible mechanisms for amyloid disaggregation by CyP40. Based on our structural data( Fig 8A), it is possible that the PPIase domain interacts with specific proline residues in β-turns and twists these residues. Given that CyP40-mediated disaggregation occurs without the input of external energy, it is possible that the disaggregation reaction energy comes from the PPIase domain of CyP40 binding to key residues within the amyloid substrate followed by a conformational switch within the TPR domain( Fig 8C). There is precedent for disaggregation independent of external energy as described for the plant chaperone, cpSRP43[41]. Because of the equimolar amount of substrate and CyP40 used in the ThT-monitored disaggregation experiments, an alternative mechanism could be proposed. In this hypothesis, CyP40 may interact with and sequester small oligomers and monomers away from the aggregation equilibrium( see Fig 8D). However, this hypothesis does not explain the lack of disaggregation activity in the PPIase-null CyP40. Therefore, further experiments are required to determine the precise mechanism by which CyP40 disaggregation occurs. It should be noted that the 2 proposed models become the same if CyP40 remains bound to the substrate. Though CyP40 can directly interact with Hsp90 through a TPR domain, the effects described here do not appear to be Hsp90 dependent. In fact, the PPIase activity of CyP40 is reduced upon interaction with Hsp90[23]. This may explain why tau fibrils were only disaggregated upon the overexpression of CyP40. Further studies are required to determine if there are endogenous mechanisms to increase CyP40 activity either through the up-regulation of CyP40 expression, by increasing CyP40 stability, or by increasing the enzymatic activity of CyP40. Recent work suggests that upon cellular stress Hsp90 may dissociate from CyP40, leading to an increased pool of more catalytically active CyP40[23]. This may hint at a possible mechanistic pathway by which CyP40 may be “turned on” in response to stress, including toxic amyloid build-up. In addition to CyP40, there are currently 41 known human PPIases within the cyclophilin, FKBP, and parvulin families. Therefore, future screening may reveal additional PPIases with activities similar to CyP40, including ATP-independent disaggregation. Additionally, CyP40 and other PPIases should be further characterized for disaggregation activity against proline-containing amyloids, especially those associated with disease.
Inside 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 chaperones also prevent the aggregation of newly formed proteins and can shunt misfolded proteins toward degradation pathways . In addition to interacting with newly synthesized proteins , chaperones also help to maintain cellular homeostasis by triaging toxic protein aggregates , which are responsible for causing neurodegenerative diseases . Two proteins that can form these toxic aggregates are tau and α-synuclein , which form tangles in Alzheimer’s disease and Lewy bodies in Parkinson’s disease , respectively . These proteins aggregate to form small , soluble aggregates termed oligomers and long fibrils often termed amyloids , both of which are thought to be toxic . Here we show that a chaperone , cyclophilin 40 ( CyP40 ) , interacts with and dissolves tau and α-synuclein aggregates . CyP40 may accomplish this by interacting with proline residues in these proteins , which are known to play a key role in fibril stability . We show that CyP40 both lowers tau fibrils and oligomers in mice that overexpress tau protein and preserves cognition in these transgenic animals .