PLASMINOGEN STIMULATES FORMATION OF PATHOGENIC PRION CLUMPS
ABSTRACT
Prion diseases are associated with the conversion of the normal prion protein, PrPC, to the infectious disease form PrPSc. Discrimination between these isoforms would significantly enhance diagnosis of these diseases, and it has recently been reported that PrPSc is specifically recognized by the serine protease zymogen plasminogen (Fischer et al. (2000) Nature 408, 479). Here we have tested the hypothesis that PrP is a regulator of the plasminogen activation system. The effect of recombinant PrP, either containing copper (holo-PrP) or devoid of it (apo-PrP), on plasminogen activation by both uPA and tPA was determined. PrP had no effect on plasminogen activation by uPA. By contrast, the activity of tPA was stimulated by up to 280-fold. This was observed only with the apo-PrP isoforms.
The copper-binding octapeptide repeat region of PrP was involved in the effects, as a mutant lacking this region failed to stimulate plasminogen activation, although a synthetic peptide corresponding to this region was unable to stimulate tPA activity. Competition experiments demonstrated that, in addition to plasminogen binding, the stimulation required a high-affinity interaction between tPA and PrP (Kd < 2.5 nM). Kinetic analysis revealed a template mechanism for the stimulation, suggesting independent binding sites for tPA and plasminogen. Lack of copper-binding may be an early event in the conversion of PrPC to PrPSc, and our data therefore suggest that tPA-catalyzed plasminogen activation may provide the basis for a sensitive detection system for the early stages of prion diseases and also play a role in the pathogenesis of these diseases.
CHAPTER ONE
Introduction
1.1 Background of the Study
Prion diseases are fatal neurodegenerative conditions, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy and scrapie in animals. They are characterized by the accumulation in the brain of an abnormal isoform of the prion protein (PrPSc)1 in amyloid deposits (1). The normal prion protein (PrPC) is a glycoprotein expressed on the plasma membrane as a GPI-anchored protein and highly concentrated in synapses (2). PrPSc, which is rich in -sheets, is generated from the largely R-helical PrPC by a conversion mechanism as yet unknown (3).
Prion diseases can all be experimentally transmitted to other animals, and PrPSc is inseparable from the infectious agent. The expression of PrPC is necessary for prion disease, as mice devoid of PrPC are resistant to infection (4). The generation of PrPSc from host PrPC implies that the mechanism by which PrPSc is generated is of fundamental importance in understanding the cause of these diseases and that understanding the difference between PrPC and PrPSc might lead to both diagnosis and possibly treatment of prion diseases. One significant difference between these proteins that has recently been described by Fischer et al. (5) is that some plasma proteins, notably plasminogen, bind to PrPSc but not to PrPC.
Several studies have demonstrated that PrPC is a copperbinding protein (6-9). However, recent studies have indicated that PrPSc does not bind copper. PrP isolated from mouse brains contains approximately 3 copper atoms per PrP molecule, and a further 2 atoms can be bound in vitro (10). In contrast, PrP isolated from brains of both scrapie-infected mice and humans with Creutzfeldt-Jakob disease contains less than 0.5 copper atoms per PrP molecule (11). Copper binding is thought to have both functional and structural effects on PrP. Copper both increases the rate of endocytosis of PrPC (12) and endows it with superoxide dismutase activity (9, 10). The N-terminal half of PrP contains four tandem copies of a highly conserved octapeptide repeat which is thought to bind copper by coordination to four histidine residues (13). This binding of copper impacts structure in this otherwise unstructured part of the molecule (14). Copper can be specifically incorporated into recombinant PrP (PrP23-231), but not PrP lacking the octapeptide repeat region (PrP?51-90), during the refolding procedure and acquire properties resembling those of PrPC (9, 15).
Pericellular proteolytic activity plays an important role in many pathological as well as physiological situations in a variety of organs, including the brain. This proteolytic activity can act to degrade components of the extracellular matrix or activate bioactive molecules such as growth factors, making it a key regulator of cellular behavior (16). The broad specificity serine protease plasmin is one of the principal activities involved in these processes. Plasmin is generated from the abundant zymogen plasminogen by a single proteolytic cleavage catalyzed by either of the two plasminogen activators, uPA and tPA. At the functional level, the activity of the plasminogen activation system is largely regulated by mechanisms that enhance the generation of plasmin (17).
Thus uPA-catalyzed plasminogen activation is stimulated by the binding of uPA to its cell surface receptor uPAR (18) and tPA-catalyzed plasminogen activation by binding to fibrin (19) or cell surface binding sites (20). All of these situations involve the binding of plasminogen in juxtaposition to the plasminogen activator, either on the same cofactor molecule (as with fibrin) or to discrete cellular binding sites. Interactions with these molecules are mediated by “lysine binding sites” in the kringle modules of plasminogen, which can be antagonized by lysine and various aminocarboxylic acid analogues of lysine, such as ACA (21). These kringle modules preferentially bind C-terminal lysine residues (i.e., those with a free carboxylate group), which can either be present in the native proteins or generated by the proteolytic action of plasmin.
1.2 Statement Problem
The ?brinolytic system has been implicated in multiple biological functions such as wound healing, angiogenesis, tumor metastasis and brain development [1− 3]. In addition to their biological functions, plasminogen activators are routinely used for therapeutic interventions in acute arterial thrombosis such as myocardial infarction [4] and stroke [5]. Several plasminogen activators with distinct biochemical properties are in clinical use. First generation ?brinolytic agents are strepto- kinase, anisoylated plasminogen-streptokinase activator complex (APSAC), urokinase, single chain urokinase and tissue-type plasminogen activator. Apart from tissue-type plasminogen activator (t-PA), none of the ?rst generation ?brinolytic agents bind to ?brin and induce systemic plasmi- nogen activation with pronounced changes in the concentra- tions of hemostatic and ?brinolytic proteins.
By contrast, t-PA has a stringent cofactor requirement to protect the organism from the detrimental consequences of non-speci?c plasminogen activation. The formation of a ternary complex with ?brin and plasminogen is required to stimulate t-PA activity [6]. This ?brin speci?city of t-PA is concentration dependent. At the concentrations used in ?brinolytic therapy, a systemic activation of the ?brinolytic system is still detectable as evidenced by consumption of hemostatic and ?brinolytic proteins. Nevertheless, this consumption is much less pro- nouncedcomparedwith the other ?rst generation thrombolytic agents.
Here we test the hypothesis that, due to its reported ability to bind plasminogen, PrPSc is a regulator of plasminogen activation. We demonstrate that PrP can indeed regulate plasminogen activation but that, surprisingly, a critical determinant of this is an interaction between PrP and tPA. Furthermore, rather than being a result of the conversion of PrPC to PrPSc, the ability of PrP to interact with tPA and plasminogen, and to stimulate plasminogen activation, is related to the binding of copper to PrP. These data have implications for the diagnostic detection of the prion diseases and suggest that plasmin may have a role in prion-induced neurodegeneration.
1.3 Research Objective
The objective of this study was to evaluate the plasminogen stimulates formation of pathogenic prion clumps.
CHAPTER TWO
2.0 Literature Review
2.1 Introduction
The review of relevant literature is the main topic of this chapter. A literature review covers theoretical and methodological contributions to a certain issue in addition to the state of knowledge at the time of writing. It provides information about the state of the art in relation to the subject you are writing about. It examines the body of work on the chosen subject. The literature evaluation in this study comprises the …
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TABLE OF CONTENTSPRELIMINARY PAGES
- Title page
- Approval page
- Dedication
- Acknowledgement
- Table of Contents
- Abstract
- 1.0 Introduction
- 1.1 Background Of The Study
- 1.2 Statement Problem
- 1.3 Research Objective
- 2.0 Review Of Related Literature
- 2.1 Conceptual Review
- 2.2 Empirical Review
- 3.0 Methodology
- 4.0 Descriptive And Empirical Results
- 5.0 Conclusion And Recommendation
- REFERENCES
Disclaimer for Complete Material Utilization
The displayed research work titled "Plasminogen Stimulates Formation of Pathogenic Prion Clumps" is stated as a research guideline towards accomplishing your assigned project / seminar research work. All the research materials on this website are ONLY for research purposes and should be used as a guideline in developing your research work. For no reason should you copy word for word as projectlist.com.ng will not be liable for any who copied the material. By ordering the complete research guideline, it signifies that you've accepted our terms of service.
PRELIMINARY PAGES
- Title page
- Approval page
- Dedication
- Acknowledgement
- Table of Contents
- Abstract
- 1.0 Introduction
- 1.1 Background Of The Study
- 1.2 Statement Problem
- 1.3 Research Objective
- 2.0 Review Of Related Literature
- 2.1 Conceptual Review
- 2.2 Empirical Review
- 3.0 Methodology
- 4.0 Descriptive And Empirical Results
- 5.0 Conclusion And Recommendation
- REFERENCES
Disclaimer for Complete Material Utilization
The displayed research work titled "Plasminogen Stimulates Formation of Pathogenic Prion Clumps" is stated as a research guideline towards accomplishing your assigned project / seminar research work. All the research materials on this website are ONLY for research purposes and should be used as a guideline in developing your research work. For no reason should you copy word for word as projectlist.com.ng will not be liable for any who copied the material. By ordering the complete research guideline, it signifies that you've accepted our terms of service.
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