Research identifies drug target for prion diseases, ‘mad cow’

LEXINGTON, Ky. (Jan. 4, 2011) − Scientists at the University of Kentucky have discovered that plasminogen, a protein used by the body to break up blood clots, speeds up the progress of prion diseases such as mad cow disease.

This finding makes plasminogen a promising new target for the development of drugs to treat prion diseases in humans and animals, says study senior author Chongsuk Ryou, a researcher at the UK Sanders-Brown Center on Aging and professor of microbiology, immunology and molecular genetics in the UK College of Medicine.

“I hope that our study will aid in developing therapy for prion diseases, which will ultimately improve the quality of life of patients suffering from prion diseases,” Ryou said. “Since prion diseases can lay undetected for decades, delaying the ability of the disease-associated prion protein to replicate by targeting the cofactor of the process could be a monumental implication for treatment.”

The study was reported in the December issue of The FASEB Journal (www.fasebj.org), published by the Federation of American Societies for Experimental Biology.

Ryou’s team used simple test-tube reactions to multiply disease-associated prion proteins. The reactions were conducted in the presence or absence of plasminogen. They also found that the natural replication of the prions was stimulated by plasminogen in animal cells.

“Rogue prions are one of nature’s most interesting, deadly and least understood biological freak shows,” says Dr. Gerald Weissmann, editor-in-chief of The FASEB Journal. “They are neither virus nor bacteria, but they kill or harm you just the same. By showing how prions hijack our own clot-busting machinery, this work points to a new target for anti-prion therapy.”

According to the U.S. National Institute of Allergy and Infectious Diseases, prion diseases are a related group of rare, fatal brain diseases that affect animals and humans. The diseases are characterized by certain misshapen protein molecules that appear in brain tissue. Normal forms of these prion protein molecules reside on the surface of many types of cells, including brain cells, but scientists do not understand what normal prion protein does. On the other hand, scientists believe that abnormal prion protein, which clumps together and accumulates in brain tissue, is the likely cause of the brain damage that occurs. Scientists do not have a good understanding of what causes the normal prion protein to take on the misshapen abnormal form.

Prion diseases are also known as transmissible spongiform encephalopathies, and include bovine spongiform encephalopathy (“mad cow” disease) in cattle; Creutzfeldt-Jakob disease in humans; scrapie in sheep; and chronic wasting disease in deer and elk. These proteins may be spread through certain types of contact with infected tissue, body fluids, and possibly, contaminated medical instruments.

The co-author of the study is Charles E. Mays, formerly a graduate student in the Ryou lab.

5 COMMENTS

  1. Continued….
    NOTE; The molecular bases for prion diseases are not yet fully understood. Why are some proteins infectious while others are not? Writing in the journal Angewandte Chemie, the researchers ( 2008) report that the molecular structures of the infectious and non-infectious forms are very different. Prions usually consist of β-sheet structures. These are accordion-like folded protein ribbons that can easily aggregate into thread-like structures, known as amyloid fibrils, which are present in the brains of CJD and Alzheimer’s sufferers“.
    In addition (to the alternative „BSE ammonia- magnesium theory“) , to investigate the role of regular PrP, researchers at the University of Calgary (ZAMPONI et al., 2008) looked at communication among the brain cells of PrP-free mice. When the nerve cells received the messenger glutamate, they went into hyperactive mode, repeatedly firing as if the message had been shouted at them. These overexcited cells were more likely to die because of this overactivation. Normal PrP protein might function to block some N-methyl-D-aspartate (NMDA) receptors and thereby prevent overexcitement of neurons.The researchers also removed magnesium (Mg) from the cells. Without it, the brain cells went into seizure mode…

  2. Continued….
    With the regard to the antagonism of calcium and magnesium, on this poster presentation- see my website, I wrote the following;

    „Under normal conditions of synaptic transmission, the NMDA receptor channel is blocked by Mg2+ sitting in the channel and only activated for brief periods of time. Under pathological conditions, however, overactivation of the receptor causes an excessive amount of Ca2+ influx into the nerve cell, which then triggers a variety of processes. Energetically compromised neurons become depolarized (more positively charged) because in the absence of energy they cannot maintain ionic homeostasis; this depolarization relieves the normal Mg2+ block of NMDA receptor-coupled channels because the relatively positive charge in the cell repels positively-charged Mg2+ from the channel pore.
    Hence, during periods in many neurodegenerative diseases, excessive stimulation of
    glutamate receptors is thought to occur. These neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease…, are caused by different mechanisms but may share a final common pathway to neuronal injury due to the overstimulation of glutamate receptors, especially of the NMDA subtype
    An important consequence of NMDAR activation is the influx of Ca2+ into
    neurons. Excessive NMDAR stimulation is thought to be an important factor in neuronal cell damage, mediated by excessive Ca entry into the cell. Mg competes with Ca at voltage- gated Ca channels both intracellularly and on the cell surface membrane.
    Continued….

  3. Continued…
    It is already 10 years (March 2001), when I wrote the study, which shows that mad cow disease (BSE) is not an infectious disease! WHY? Because, it was due to the climatic conditions (humid coastal climate), prevailing grasses responding favorably to sufficient moisture (English ryegrass), and high consumption of nitrogenous fertilizers, created ideal conditions for magnesium deficiency in ruminants- in Great Britain during the 80th years. Why? Because the magnesium in ruminants, unlike all the animals, is not absorbed in the intestine, but in the rumen. So when excess of protein in the diet of ruminants, creating an insoluble, and non-absorbable magnesium ammonium phosphate. So as the cause of BSE, I wrote the following diagnosis (March 2001), long-term protein excess intake, and insufficient utilization of magnesium. So in the connection with the protein surpluss, ruminants are predominant about the Mg- deficiency, so BSE can be involved (alternative „BSE ammonia- magnesium theory).
    Later in August 2006 I have an alternative theory that the BSE has published on the my website http://www.bse.expert.cz , in 2008 I was informed about that “BSE alternative theory” as the poster presentation at 29th World Veterinary Congress in Vancouver, named; Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors (http://www.bse-expert.cz/pdf/Veter_kongres.pdf).
    Continued….

  4. So scientists have discovered that a protein plasminogen, speeds up the progress of prion diseases such as mad cow disease. They found that the natural replication of the prions (from PrP to PrPSc) was stimulated by plasminogen in both human and animal cells. To clarify the role of plasminogen as a cofactor for prion propagation, they conducted functional assays using a cell-free prion protein (PrP) conversion assay termed protein misfolding cyclic amplification (PMCA) and prion-infected cell lines. They report that plasminogen stimulates propagation of the protease-resistant scrapie PrP (PrPSc). Compared to control PMCA conducted without plasminogen, addition of plasminogen in PMCA using wild-type brain material significantly increased PrP conversion. Their results demonstrate that plasminogen functions in stimulating conversion processes and represents the first cellular protein cofactor that enhances the hypothetical mechanism of prion propagation.
    However, the serine protease, tissue-type plasminogen activator (tPA), is known for its ability to cleave the pro-enzyme plasminogen into the potent protease plasmin. The”tPA” is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding NMDA receptor (NMDAR). As a result, several recent studies which show interplay between tPA and the NMDAR have received considerable attention A persuasive body of evidence suggests that tPA can directly (i.e. in a plasmin-independent manner) cleave the NR1 subunit and thereby increase the Ca2+-permeability of the NMDAR.
    Continued….

  5. So scientists have discovered that a protein plasminogen, speeds up the progress of prion diseases such as mad cow disease. They found that the natural replication of the prions (from PrP to PrPSc) was stimulated by plasminogen in both human and animal cells. To clarify the role of plasminogen as a cofactor for prion propagation, they conducted functional assays using a cell-free prion protein (PrP) conversion assay termed protein misfolding cyclic amplification (PMCA) and prion-infected cell lines. They report that plasminogen stimulates propagation of the protease-resistant scrapie PrP (PrPSc). Compared to control PMCA conducted without plasminogen, addition of plasminogen in PMCA using wild-type brain material significantly increased PrP conversion. Their results demonstrate that plasminogen functions in stimulating conversion processes and represents the first cellular protein cofactor that enhances the hypothetical mechanism of prion propagation.
    However, the serine protease, tissue-type plasminogen activator (tPA), is known for its ability to cleave the pro-enzyme plasminogen into the potent protease plasmin. The”tPA” is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding NMDA receptor (NMDAR). As a result, several recent studies which show interplay between tPA and the NMDAR have received considerable attention A persuasive body of evidence suggests that tPA can directly (i.e. in a plasmin-independent manner) cleave the NR1 subunit and thereby increase the Ca2+-permeability of the NMDAR.
    It is already 10 years (March 2001), when I wrote the study, which shows that mad cow disease (BSE) is not an infectious disease! WHY? Because, it was due to the climatic conditions (humid coastal climate), prevailing grasses responding favorably to sufficient moisture (English ryegrass), and high consumption of nitrogenous fertilizers, created ideal conditions for magnesium deficiency in ruminants- in Great Britain during the 80th years. Why? Because the magnesium in ruminants, unlike all the animals, is not absorbed in the intestine, but in the rumen. So when excess of protein in the diet of ruminants, creating an insoluble, and non-absorbable magnesium ammonium phosphate. So as the cause of BSE, I wrote the following diagnosis (March 2001), long-term protein excess intake, and insufficient utilization of magnesium. So in the connection with the protein surpluss, ruminants are predominant about the Mg- deficiency, so BSE can be involved (alternative „BSE ammonia- magnesium theory).
    Later in August 2006 I have an alternative theory that the BSE has published on the my website http://www.bse.expert.cz , in 2008 I was informed about that “BSE alternative theory” as the poster presentation at 29th World Veterinary Congress in Vancouver, named; Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors (http://www.bse-expert.cz/pdf/Veter_kongres.pdf).

    With the regard to the antagonism of calcium and magnesium, on this poster presentation- see my website, I wrote the following;

    „Under normal conditions of synaptic transmission, the NMDA receptor channel is blocked by Mg2+ sitting in the channel and only activated for brief periods of time. Under pathological conditions, however, overactivation of the receptor causes an excessive amount of Ca2+ influx into the nerve cell, which then triggers a variety of processes. Energetically compromised neurons become depolarized (more positively charged) because in the absence of energy they cannot maintain ionic homeostasis; this depolarization relieves the normal Mg2+ block of NMDA receptor-coupled channels because the relatively positive charge in the cell repels positively-charged Mg2+ from the channel pore.
    Hence, during periods in many neurodegenerative diseases, excessive stimulation of
    glutamate receptors is thought to occur. These neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease…, are caused by different mechanisms but may share a final common pathway to neuronal injury due to the overstimulation of glutamate receptors, especially of the NMDA subtype
    An important consequence of NMDAR activation is the influx of Ca2+ into
    neurons. Excessive NMDAR stimulation is thought to be an important factor in neuronal cell damage, mediated by excessive Ca entry into the cell. Mg competes with Ca at voltage- gated Ca channels both intracellularly and on the cell surface membrane
    NOTE; The molecular bases for prion diseases are not yet fully understood. Why are some proteins infectious while others are not? Writing in the journal Angewandte Chemie, the researchers ( 2008) report that the molecular structures of the infectious and non-infectious forms are very different. Prions usually consist of β-sheet structures. These are accordion-like folded protein ribbons that can easily aggregate into thread-like structures, known as amyloid fibrils, which are present in the brains of CJD and Alzheimer’s sufferers“.

    In addition (to the alternative „BSE ammonia- magnesium theory“) , to investigate the role of regular PrP, researchers at the University of Calgary (ZAMPONI et al., 2008) looked at communication among the brain cells of PrP-free mice. When the nerve cells received the messenger glutamate, they went into hyperactive mode, repeatedly firing as if the message had been shouted at them. These overexcited cells were more likely to die because of this overactivation. Normal PrP protein might function to block some N-methyl-D-aspartate (NMDA) receptors and thereby prevent overexcitement of neurons.The researchers also removed magnesium (Mg) from the cells. Without it, the brain cells went into seizure mode…

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