Prion switching in response to environmental stress

Nov 25, 2008

If you have had a hard day at work, you may change your eating habits, perhaps favoring comfort food, but you don't suddenly develop the ability to eat the plate and cutlery. A new paper, published in this week's issue of PLoS Biology, describes an evolutionary mechanism in yeast that allows cells to respond to environmental stress in novel ways, including digesting materials that they were previously unable to use – though admittedly, they aren't eating crockery just yet! The work shows that a protein-misfolding mechanism that can reveal hidden genetic variation is far more likely to be triggered when yeast is under environmental stress, and is therefore an evolutionary strategy to trigger rapid evolution.

All animal cells contain DNA that is never used, which includes old copies of genes that have become defunct during the evolutionary process, and even parasitic bits of DNA introduced by viruses that now lie dormant. It has been suggested by evolutionary theorists that difficult environmental conditions would favour organisms that have increased 'evolvability' – i.e. those that are capable of adapting rapidly to the environment. One way of having increased 'evolvability' is to utilize some of the variation encoded in this unused DNA. A new paper, by Dr. Susan Lindquist and colleagues at the Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, suggests that such a mechanism exists in yeast, a mechanism based on the presence of a prion called [PSI+].

Best known as the infectious agents in mad cow disease, prions also can play positive roles in biology, the scientists emphasize. "A prion is not necessarily detrimental; in yeast it can be a different way for a cell to code information," says Jens Tyedmers a lead author. In yeast, the [PSI+] prion is a mis-folded version of a protein that plays a key role in making other proteins. Earlier studies showed that the presence of [PSI+] in a yeast cell changes protein production such that hidden genetic variations are included in the proteins that a cell produces. Most of the resulting phenotypes (variants of the organism) have no effect on cell survival, or make things worse. "But about a quarter of the time, the phenotypes are good," says Lindquist. "Sometimes the yeast can grow on energy sources it couldn't grow on before, or withstand antibiotics it couldn't withstand."

This heightened ability to adapt to changing environments may be maintained in yeast as a way to accelerate evolutionary changes. Under stress, yeast cells can unleash a remarkable mechanism based on these misfolded proteins that give them new characteristics without a prior genetic mutation. This mechanism is triggered much more often as the cells undergo stress, suggesting that it is tailored to play exactly this role in evolution.

To test their hypothesis, the scientists first examined what genes might help to induce the prion state, plowing through the entire genome of Saccharomyces cerevisiae, the common baker's yeast that biologists have studied intensively for many years. Tyedmers tested 4700 yeast strains that each lacked one of the genes in the yeast genome, and then tested each strain's ability to create the prion. Among the strains most successful at generating prions, many had changes in regulating the response of a cell to stress.

With that encouragement, Maria Lucia Madariaga, another lead author on the paper, went on to do stress tests on the yeast. Madariaga notes,"We wanted to use some conditions you would find in nature. Yeast hanging out in a vineyard are subject to heat, salt and other stresses."

They found that the more stress experienced by the organism, the more likely it is to flip into a prion state. Otherwise, "when things are hunky-dory, only one in a million yeast cells flips into the prion state," observes Lindquist.

That finding helps to make the case that this mechanism aids in accelerating evolution. "It's always difficult to prove any argument about how a mechanism evolved, but this does offer a coherent logical story," she says.

Citation: Tyedmers J, Madariaga ML, Lindquist S (2008) Prion switching in response to environmental stress. PLoS Biol 6(11): e294. doi:10.1371/journal.pbio.0060294
biology.plosjournals.org/perls… journal.pbio.0060294

Source: Public Library of Science

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JosefHlasny
3 / 5 (1) Nov 26, 2008
In your article Prion switching response to environmental stres? you wrote; Under stress, yeast cells can unleash a remarkable mechanism based on these misfolded proteins that give them new charasteristics without a prior genetic mutation... So also animal body cells can unleash these mechanisms under dietary protein-surpluss stress. There is one example according to my recent presentation at 29th World Veterinary Congress in Vancouver (www.bse-expert.cz]www.bse-expert.cz[/url]/pdf/Veter_kongres.pdf);]http://www.bse-ex...es.pdf);[/url]
Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors. There is the abstract about this article;
Neurodegenerative diseases, including BSE, Alzheimer%u2019s disease etc. 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 N-methyl-D -aspartate (NMDA) receptor subtype. It is generally accepted that the influx of Ca2 as a result of excessive activation of the NMDA receptor underlies the toxic actions of glutamate in many systems. Also, ammonia intoxication leads to excessive activation of NMDA receptors in brain. On the other hand, Mg2 competes with Ca2 at voltage- gated calcium channels both intracellularly and on the cell surface membrane. So, Mg2 can protect against NMDA- induced neurodegeneration and Ca2 deficiency can be important about "NMDA hypofunction" in schizophrenia.
There are no scientific references to date in which high intake of crude protein (and potassium) high enough to lead to a state of hyperammonemia (and hypomagnesemia) during the incubation period of the BSE. Therefore there is the first idea of this review; to show the hyperammonemia plus hypomagnesemia"simultaneo us" action on the ruminant tissues.
Recently was found that elevated manganese in blood was associated with "prion infection" in ruminants. These findings about "manganese theory" act in concert with this "BSE ammonia- magnesium theory".
Comments about this abstract; as a proof concerning Mg-deficiency (and hepatopathy; see www.bse-expert.cz]www.bse-expert.cz[/url] ), according to the alternative BSE ammonia- magnesium theory;
1. In biological systems, only Mn2 is readily capable of replacing Mg2 , and only in a limited set of circumstances. The body can replace Mn with Mg with similar efficiency in Mn-activated proteins (1990). Similarly, Mn can occupy Mg allosteric sites in Mg-activated proteins, such as the sarcoplasmic reticulum Ca- ATPase (1981). It was found (1999) that feeding rats a diet deficient in Mg; decreased urinary - fecal Mn excretion and greater Mn retention in skeletal muscle, heart and kidney (except the liver and trabecular bone) in Mg-deficient rats was observed.
2. Other cause about Mn deposits in tissues is liver disease. People with chronic liver disease have neurological pathology and behavioral signs of Mn neurotoxicity, probably because elimination of Mn in bile is impaired (1994- 1996). This impairment results in higher circulating concentrations of Mn, which then has access to the brain via transferrin. It was reported that whole blood Mn concentrations significantly increased in patients with chronic liver disease.
Comments about recent %u201ECanada experiments%u201C as another confirmation about the BSE ammonia- magnesium theory (hyperammonemia-proteinemia and hypomagnesemia) in the neurodegeneration;
Normal prion protein (PrPc) might function to block some NMDA receptors and thereby prevent overexcitement and death of neurons. Recently researchers at the University of Calgary (April, 2008) found; when the nerve cells received the messenger glutamate, they went into hyperactive mode, however, when also Mg was removed from the cells, the brain cells went into seizure mode.
In addition also another neurodegenerative CWD can be a naturally occurring disease. See the Chapter; Prions are a symptom of the (metabolic) chronic wasting disease and do not cause the disease in my web www.bse-expert.cz]www.bse-expert.cz[/url] (http://www.bse-expert.cz]www.bse-expert.cz[/url]/pdf/CWD_Deer.pdf). My recommendation about this theory testation;
There is necessary to make fertilization trial and take your U.S. recommendations into the practice (http://www.pfmt.o...on.htm); Fertilization of cool-season grasses (ryegrass%u2026) should coincide with spring green-up; so apply ammonium nitrate at a rate of 100 pounds per acre (112 kg of N / ha as NH4NO3). White-tailed deer need a minimum of 17% crude protein (CP) in their forage year-round , so keep the level of 17- 20% CP in forage (repeated N fertilization) during a mininimum of six months.Take into practice also other %u201EU.S. recommendations%u201C for the captive deer herds (http://www.sweene...?cat=5); Whitetail deer need protein all year round, so automatic Protein Feeders are totally dependable%u2026 So keep the level of 20% CP in the protein concentrate (with soya bean meal) during a mininimum of six months! I am sure that the CWD will be developed in some animals... WHY? Because also 13% ; six from the 47 experimental dairy cows developed clinical signs of BSE; after six month incubation period; without meat and bone meal, however, with high protein concentrate feeding. See a nutritonal experiment performed in England; published in Veterinary Record (MOORBY et al., 2000) and in Journal of Dairy Science ( DEWHURST et al., 2000; MOORBY et al., 2000).
So in conclusion; Can be Spongiform encephalopathies- as a loss of parasympathetic function according to the alternative BSE ammonia- magnesium theory (http://www.bse-expert.cz]www.bse-expert.cz[/url]/pdf/Vegetative_CNS.pdf)? See also these relationships published in Feed Mix more than six years ago (http://www.warmwe...e_debate[1].pdf).
Sincerely,
Josef Hlasny, DVM, PhD, Czech Republic
JosefHlasny
1 / 5 (1) Nov 26, 2008
In your article Prion switching response to environmental stres? you wrote; Under stress, yeast cells can unleash a remarkable mechanism based on these misfolded proteins that give them new charasteristics without a prior genetic mutation... So also animal body cells can unleash these mechanisms under dietary protein-surpluss stress. There is one example according to my recent presentation at 29th World Veterinary Congress in Vancouver
(www.bse-expert.cz]www.bse-expert.cz[/url]/pdf/Veter_kongres.pdf);]http://www.bse-ex...es.pdf);[/url]
Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors. There is the abstract about this article;
Neurodegenerative diseases, including BSE, Alzheimer%u2019s disease etc. 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 N-methyl-D -aspartate (NMDA) receptor subtype. It is generally accepted that the influx of Ca2 as a result of excessive activation of the NMDA receptor underlies the toxic actions of glutamate in many systems. Also, ammonia intoxication leads to excessive activation of NMDA receptors in brain. On the other hand, Mg2 competes with Ca2 at voltage- gated calcium channels both intracellularly and on the cell surface membrane. So, Mg2 can protect against NMDA- induced neurodegeneration and Ca2 deficiency can be important about "NMDA hypofunction" in schizophrenia.
There are no scientific references to date in which high intake of crude protein (and potassium) high enough to lead to a state of hyperammonemia (and hypomagnesemia) during the incubation period of the BSE. Therefore there is the first idea of this review; to show the hyperammonemia plus hypomagnesemia"simultaneo us" action on the ruminant tissues.
Recently was found that elevated manganese in blood was associated with "prion infection" in ruminants. These findings about "manganese theory" act in concert with this "BSE ammonia- magnesium theory".
Comments about this abstract; as a proof concerning Mg-deficiency (and hepatopathy; see www.bse-expert.cz]www.bse-expert.cz[/url] ), according to the alternative BSE ammonia- magnesium theory;
1. In biological systems, only Mn2 is readily capable of replacing Mg2 , and only in a limited set of circumstances. The body can replace Mn with Mg with similar efficiency in Mn-activated proteins (1990). Similarly, Mn can occupy Mg allosteric sites in Mg-activated proteins, such as the sarcoplasmic reticulum Ca- ATPase (1981). It was found (1999) that feeding rats a diet deficient in Mg; decreased urinary - fecal Mn excretion and greater Mn retention in skeletal muscle, heart and kidney (except the liver and trabecular bone) in Mg-deficient rats was observed.
2. Other cause about Mn deposits in tissues is liver disease. People with chronic liver disease have neurological pathology and behavioral signs of Mn neurotoxicity, probably because elimination of Mn in bile is impaired (1994- 1996). This impairment results in higher circulating concentrations of Mn, which then has access to the brain via transferrin. It was reported that whole blood Mn concentrations significantly increased in patients with chronic liver disease.
Comments about recent %u201ECanada experiments%u201C as another confirmation about the BSE ammonia- magnesium theory (hyperammonemia-proteinemia and hypomagnesemia) in the neurodegeneration;
Normal prion protein (PrPc) might function to block some NMDA receptors and thereby prevent overexcitement and death of neurons. Recently researchers at the University of Calgary (April, 2008) found; when the nerve cells received the messenger glutamate, they went into hyperactive mode, however, when also Mg was removed from the cells, the brain cells went into seizure mode.
In addition also another neurodegenerative CWD can be a naturally occurring disease. See the Chapter; Prions are a symptom of the (metabolic) chronic wasting disease and do not cause the disease in my web www.bse-expert.cz]www.bse-expert.cz[/url] (http://www.bse-expert.cz]www.bse-expert.cz[/url]/pdf/CWD_Deer.pdf). My recommendation about this theory testation;
There is necessary to make fertilization trial and take your U.S. recommendations into the practice (http://www.pfmt.o...on.htm); Fertilization of cool-season grasses (ryegrass%u2026) should coincide with spring green-up; so apply ammonium nitrate at a rate of 100 pounds per acre (112 kg of N / ha as NH4NO3). White-tailed deer need a minimum of 17% crude protein (CP) in their forage year-round , so keep the level of 17- 20% CP in forage (repeated N fertilization) during a mininimum of six months.Take into practice also other %u201EU.S. recommendations%u201C for the captive deer herds (http://www.sweene...?cat=5); Whitetail deer need protein all year round, so automatic Protein Feeders are totally dependable%u2026 So keep the level of 20% CP in the protein concentrate (with soya bean meal) during a mininimum of six months! I am sure that the CWD will be developed in some animals... WHY? Because also 13% ; six from the 47 experimental dairy cows developed clinical signs of BSE; after six month incubation period; without meat and bone meal, however, with high protein concentrate feeding. See a nutritonal experiment performed in England; published in Veterinary Record (MOORBY et al., 2000) and in Journal of Dairy Science ( DEWHURST et al., 2000; MOORBY et al., 2000).
So in conclusion; Can be Spongiform encephalopathies- as a loss of parasympathetic function according to the alternative BSE ammonia- magnesium theory (http://www.bse-expert.cz]www.bse-expert.cz[/url]/pdf/Vegetative_CNS.pdf)? See also these relationships published in Feed Mix more than six years ago (http://www.warmwe...e_debate[1].pdf).
Sincerely,
Josef Hlasny, DVM, PhD, Czech Republic

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