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- Smoking ‘stops’ cancer-fighting proteins, makes harder to treat the disease: Study Gulf News
- How tobacco smoking undermines anti-cancer defenses: study Arab Times Kuwait News
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Tag Archives: proteins
Molecular Mystery Solved – Harvard Scientists Discover a Previously Unknown Way Cells Break Down Proteins – SciTechDaily
- Molecular Mystery Solved – Harvard Scientists Discover a Previously Unknown Way Cells Break Down Proteins SciTechDaily
- The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation Science
- Fundamental understanding of a molecule’s normal function could inform treatments for a variety of brain disorders Medical Xpress
- Unraveling the Secrets to Brain Diseases – When Proteins Get Stuck at Solid SciTechDaily
- Scientists discover a previously unknown way cells break down proteins Phys.org
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Midnolin protein plays key role in breaking down short-lived nuclear proteins – News-Medical.Net
- Midnolin protein plays key role in breaking down short-lived nuclear proteins News-Medical.Net
- Unraveling the Secrets to Brain Diseases – When Proteins Get Stuck at Solid SciTechDaily
- The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation Science
- Fundamental understanding of a molecule’s normal function could inform treatments for a variety of brain disorders Medical Xpress
- Newly Identified Proteasomal Protein Disposal Mechanism Bypasses Ubiquitin Tagging Genetic Engineering & Biotechnology News
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‘Astonishing’ molecular syringe ferries proteins into human cells – Nature.com
- ‘Astonishing’ molecular syringe ferries proteins into human cells Nature.com
- Bacterial ‘Nanosyringe’ Could Deliver Gene Therapy to Human Cells Scientific American
- Nature’s Needle: Feng Zhang’s Team Re-engineers Bacterial “Syringes” for Programmable Protein Delivery Genetic Engineering & Biotechnology News
- Programmable protein delivery with a bacterial contractile injection system Nature.com
- DeepMind’s AI used to develop tiny ‘syringe’ for injecting gene therapy and tumor-killing drugs Livescience.com
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Free spike proteins in the blood appear to play a role in myocarditis post-COVID mRNA vaccine
Following the large-scale rollout of the messenger ribonucleic acid (mRNA) vaccines developed to prevent infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptomatic coronavirus disease 2019 (COVID-19), several cases of myocarditis were reported, mostly among healthy young people.
A recent study published in the journal Circulation examines the immunological picture in this scenario, looking for clues to the etiology of this rare and potentially serious complication.
Study: Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis. Image Credit: Design_Cells / Shutterstock
Introduction
The development of myocarditis following mRNA vaccination is rare, occurring in <2 per 100,000 individuals. It remains an unpredictable mysterious occurrence. Some have suggested that it is linked to the overproduction of antibodies or abnormal immune responses.
Autoantibody production due to polyclonal B cell activation and proliferation has also been suggested, as has immune complex formation and inflammation. Finally, some think that cardiac antigens closely resembling the spike protein are targeted by autoantibodies formed as a result of molecular mimicry.
The immune response to these vaccines in these patients needs to be better understood in order to determine why and how it happens. It is imperative to study the role of male hormones since young male patients are most often affected.
The researchers in this study looked at blood samples from 16 myocarditis patients, confirmed to have high levels of serum cardiac troponin T. All developed myocarditis after receiving the COVID-19 vaccine, typically within a week of the second dose. However, a few became sick after the first dose or booster dose. Over 80% were male.
They were studied by antibody profiling, including antibodies to the virus, autoantibodies or antibodies to the virome, and the analysis of T cells specifically directed against the virus. In addition, cytokine and antigen profiles were determined. These measurements were compared with those of 45 vaccinated controls, who were of similar age and health.
What did the study show?
All subjects and controls showed a rise in anti-spike antibodies and antibodies to the receptor binding domain (RBD), of all immunoglobulin (Ig) subclasses, IgA, IgM, and IgG. Functional differences were not perceived either, with Fc effector functions being similar in both categories. In short, all vaccinated individuals showed evidence of a protective immune response against the virus.
“We found no indication that a specific antibody response is associated with myocarditis.”
Additionally, these patients did not show evidence of increased autoantibody production or antibody production against other respiratory pathogens that differed in magnitude or range from the controls.
T cells of all relevant subtypes, including naïve, memory, and effector memory T cells, showed similar distributions in both groups. T cells also showed similar proportions of spike-specific memory CD4 T cells and activated CD4 and CD8 T cells. The only exceptions were the observation of small elevations in effector memory cells and PD-1-expressing bulk CD4 T cells in the myocarditis group.
The findings indicated that antibody and T-cell responses could not distinguish between post-vaccine myocarditis subjects and vaccinated controls. The only significant difference was a slight elevation in cytokine production in the former.
The exciting difference was the high level of circulating full-length spike protein in the plasma of myocarditis patients, at a mean of ~34 pg/mL. Furthermore, the protein was not bound to antibodies and remained detectable for up to three weeks from the vaccination date. In contrast, controls did not have free spike protein in their blood.
This difference could not be attributed to poor neutralizing capacity in the myocarditis group, which showed comparable neutralization relative to the control group.
Concordantly, myocarditis patients had cytokine release patterns resembling those found in multisystem inflammatory syndrome in children (MIS-C). This might indicate that the innate immune response was overactive, leading to elevations in interleukin (IL)-8, IL-10, IL-4, IL-6, tumor necrosis factor (TNF)-α, and interferon (INF)-γ relative to healthy controls. IL-8 was most closely associated with raised cardiac troponin T and antigen levels.
Alongside, leukocytes, especially neutrophils, were at higher mean levels in this group than controls, though still within normal range.
What are the implications?
The study shows that the immunological response elicited by the mRNA vaccine was very similar in those who developed post-vaccination myocarditis and others. In other words, myocarditis could not be associated with abnormal autoantibodies, viral infections other than SARS-CoV-2, or excessive production of antibodies elicited by the mRNA vaccine.
In vaccinated patients, infection with the virus was not likely to be a cause or contributing factor for myocarditis since anti-Nucleoprotein IgG was not found in these patients.
In contrast to controls, the finding of high levels of unbound full-length spike protein in myocarditis patients may point to the mechanism by which this condition arises. Similarly, MIS-C patients had circulating SARS-CoV-2 antigens.
The spike protein appears to evade immune antibodies found at normal levels in these patients, with adequate functional and neutralization capacity. The spike may damage the cardiac pericytes or endothelium, perhaps by reducing the expression of the angiotensin-converting enzyme 2 (ACE2), reducing nitric oxide production in the endothelium, or activating inflammation via integrins, causing the endothelium to become abnormally permeable.
“Thus, the spike antigen itself, which evades antibody recognition rather than invoking immune hyperactivation, may contribute to myocarditis in these individuals.”
This finding does not amount to evidence against the benefit of vaccination with these vaccines, which effectively protect against severe COVID-19 outcomes. Therefore, current vaccine recommendations are unlikely to be altered due to these results.
“Understanding the immunopathological mechanisms associated with postvaccine myocarditis will help improve safety and guide the development of future coronavirus disease 2019 (COVID-19) vaccines. These findings also suggest that administration of anti-spike antibodies, if spike antigenemia is detected, could potentially prevent or reverse postvaccine myocarditis.”
Free spike proteins in the blood appear to play a role in myocarditis post-COVID mRNA vaccine
Following the large-scale rollout of the messenger ribonucleic acid (mRNA) vaccines developed to prevent infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptomatic coronavirus disease 2019 (COVID-19), several cases of myocarditis were reported, mostly among healthy young people.
A recent study published in the journal Circulation examines the immunological picture in this scenario, looking for clues to the etiology of this rare and potentially serious complication.
Study: Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis. Image Credit: Design_Cells / Shutterstock
Introduction
The development of myocarditis following mRNA vaccination is rare, occurring in <2 per 100,000 individuals. It remains an unpredictable mysterious occurrence. Some have suggested that it is linked to the overproduction of antibodies or abnormal immune responses.
Autoantibody production due to polyclonal B cell activation and proliferation has also been suggested, as has immune complex formation and inflammation. Finally, some think that cardiac antigens closely resembling the spike protein are targeted by autoantibodies formed as a result of molecular mimicry.
The immune response to these vaccines in these patients needs to be better understood in order to determine why and how it happens. It is imperative to study the role of male hormones since young male patients are most often affected.
The researchers in this study looked at blood samples from 16 myocarditis patients, confirmed to have high levels of serum cardiac troponin T. All developed myocarditis after receiving the COVID-19 vaccine, typically within a week of the second dose. However, a few became sick after the first dose or booster dose. Over 80% were male.
They were studied by antibody profiling, including antibodies to the virus, autoantibodies or antibodies to the virome, and the analysis of T cells specifically directed against the virus. In addition, cytokine and antigen profiles were determined. These measurements were compared with those of 45 vaccinated controls, who were of similar age and health.
What did the study show?
All subjects and controls showed a rise in anti-spike antibodies and antibodies to the receptor binding domain (RBD), of all immunoglobulin (Ig) subclasses, IgA, IgM, and IgG. Functional differences were not perceived either, with Fc effector functions being similar in both categories. In short, all vaccinated individuals showed evidence of a protective immune response against the virus.
“We found no indication that a specific antibody response is associated with myocarditis.”
Additionally, these patients did not show evidence of increased autoantibody production or antibody production against other respiratory pathogens that differed in magnitude or range from the controls.
T cells of all relevant subtypes, including naïve, memory, and effector memory T cells, showed similar distributions in both groups. T cells also showed similar proportions of spike-specific memory CD4 T cells and activated CD4 and CD8 T cells. The only exceptions were the observation of small elevations in effector memory cells and PD-1-expressing bulk CD4 T cells in the myocarditis group.
The findings indicated that antibody and T-cell responses could not distinguish between post-vaccine myocarditis subjects and vaccinated controls. The only significant difference was a slight elevation in cytokine production in the former.
The exciting difference was the high level of circulating full-length spike protein in the plasma of myocarditis patients, at a mean of ~34 pg/mL. Furthermore, the protein was not bound to antibodies and remained detectable for up to three weeks from the vaccination date. In contrast, controls did not have free spike protein in their blood.
This difference could not be attributed to poor neutralizing capacity in the myocarditis group, which showed comparable neutralization relative to the control group.
Concordantly, myocarditis patients had cytokine release patterns resembling those found in multisystem inflammatory syndrome in children (MIS-C). This might indicate that the innate immune response was overactive, leading to elevations in interleukin (IL)-8, IL-10, IL-4, IL-6, tumor necrosis factor (TNF)-α, and interferon (INF)-γ relative to healthy controls. IL-8 was most closely associated with raised cardiac troponin T and antigen levels.
Alongside, leukocytes, especially neutrophils, were at higher mean levels in this group than controls, though still within normal range.
What are the implications?
The study shows that the immunological response elicited by the mRNA vaccine was very similar in those who developed post-vaccination myocarditis and others. In other words, myocarditis could not be associated with abnormal autoantibodies, viral infections other than SARS-CoV-2, or excessive production of antibodies elicited by the mRNA vaccine.
In vaccinated patients, infection with the virus was not likely to be a cause or contributing factor for myocarditis since anti-Nucleoprotein IgG was not found in these patients.
In contrast to controls, the finding of high levels of unbound full-length spike protein in myocarditis patients may point to the mechanism by which this condition arises. Similarly, MIS-C patients had circulating SARS-CoV-2 antigens.
The spike protein appears to evade immune antibodies found at normal levels in these patients, with adequate functional and neutralization capacity. The spike may damage the cardiac pericytes or endothelium, perhaps by reducing the expression of the angiotensin-converting enzyme 2 (ACE2), reducing nitric oxide production in the endothelium, or activating inflammation via integrins, causing the endothelium to become abnormally permeable.
“Thus, the spike antigen itself, which evades antibody recognition rather than invoking immune hyperactivation, may contribute to myocarditis in these individuals.”
This finding does not amount to evidence against the benefit of vaccination with these vaccines, which effectively protect against severe COVID-19 outcomes. Therefore, current vaccine recommendations are unlikely to be altered due to these results.
“Understanding the immunopathological mechanisms associated with postvaccine myocarditis will help improve safety and guide the development of future coronavirus disease 2019 (COVID-19) vaccines. These findings also suggest that administration of anti-spike antibodies, if spike antigenemia is detected, could potentially prevent or reverse postvaccine myocarditis.”
Slow-Moving Shell of Water Can Make Parkinson’s Proteins ‘Stickier’
Summary: Water plays a key role in how proteins associated with Parkinson’s disease fold, clump or misfold.
Source: University of Cambridge
Water – which makes up the majority of every cell in the body – plays a key role in how proteins, including those associated with Parkinson’s disease, fold, misfold, or clump together, according to a new study.
When attempting to discover potential treatments for protein misfolding diseases, researchers have primarily focused on the structure of the proteins themselves.
However, researchers led by the University of Cambridge have shown that a thin shell of water is key to whether a protein begins to clump together, or aggregate, forming the toxic clusters which eventually kill brain cells.
Using a technique known as Terahertz spectroscopy, the researchers have shown that the movement of the water-based shell surrounding a protein can determine whether that protein aggregates or not.
When the shell moves slowly, proteins are more likely to aggregate, and when the shell moves quickly, proteins are less likely to aggregate. The rate of movement of the shell is altered in the presence of certain ions, such as salt molecules, which are commonly used in the buffer solutions used to test new drug candidates.
The significance of the water shell, known as the hydration or solvation shell, in the folding and function of proteins has been strongly disputed in the past. This is the first time the solvation shell has been shown to play a key role in protein misfolding and aggregation, which could have profound implications in the search for treatments.
The results are reported in the journal Angewandte Chemie International.
When developing potential treatments for protein misfolding diseases such as Parkinson’s and Alzheimer’s disease, researchers have been studying compounds which can prevent the aggregation of key proteins: alpha-synuclein for Parkinson’s disease or amyloid-beta for Alzheimer’s disease. To date however, there are no effective treatments for either condition, which affect millions worldwide.
“It’s the amino acids that determine the final structure of a protein, but when it comes to aggregation, the role of the solvation shell, which sits on the outside of a protein, has been overlooked until now,” said Professor Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology, who led the research.
“We wanted to know whether this water shell plays a role in protein behaviour – it’s been a question in the field for a while, but no one has been able to prove it.”
The solvation shell slides around on the surface of the protein, acting like a lubricant. “We wondered whether, if the movement of water molecules was slower in the solvation shell of a protein, it could slow the movement of the protein itself,” said Dr Amberley Stephens, the paper’s first author.
To test the role of the solvation shell in the aggregation of proteins, the researchers used alpha-synuclein, the key protein implicated in Parkinson’s disease. Using Teraheartz spectroscopy, a powerful technique to study the behaviour of water molecules, they were able to observe the movement of the water molecules that surround the alpha-synuclein protein.
They then added two different salts in solution to the proteins: sodium chloride (NaCl), or regular table salt, and cesium iodide (CsI). The ions in the sodium chloride – Na+ and Cl- – bind strongly to the hydrogen and oxygen ions in water, while the ions in the cesium iodide make much weaker bonds.
The researchers found that when the sodium chloride was added, the strong hydrogen bonds caused the movement of the water molecules in the solvation shell to slow down. This resulted in slower movement of the alpha-synuclein, and the aggregation rate increased. Conversely, when the cesium iodide was added, the water molecules sped up, and the aggregation rate decreased.
“In essence, when the water shell slows down, the proteins have more time to interact with each other, so they’re more likely to aggregate,” said Kaminski Schierle.
“And on the flip side, when the solvation shell moves more quickly, the proteins become harder to catch, so they’re less likely to aggregate.”
“When researchers are screening for an aggregation inhibitor for Parkinson’s disease, they will usually use a buffer composition, but there’s been very little thought on how that buffer is interacting with the protein itself,” said Stephens.
“Our results show that you need to understand the composition of the solvent inside the cell in order to mimic the conditions you have in the brain and ultimately end up with an inhibitor that works.”
“It’s so important to look at the whole picture, and that hasn’t been happening,” said Kaminski Schierle.
“To effectively test whether a drug candidate will work in a patient, you need to mimic cellular conditions, which means you need to take everything into consideration, like salts and pH levels.
See also
“The failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease.”
Funding: The research was supported in part by Wellcome, Alzheimer’s Research UK, the Michael J Fox Foundation, and the Medical Research Council (MRC), part of UK Research and Innovation (UKRI). Gabriele Kaminski Schierle is a Fellow of Robinson College, Cambridge.
About this Parkinson’s disease research news
Author: Sarah Collins
Source: University of Cambridge
Contact: Sarah Collins – University of Cambridge
Image: The image is in the public domain
Original Research: Open access.
“Decreased Water Mobility Contributes To Increased α-Synuclein Aggregation” by Gabriele Kaminski Schierle et al. Angewandte Chemie
Abstract
Decreased Water Mobility Contributes To Increased α-Synuclein Aggregation
The solvation shell is essential for the folding and function of proteins, but how it contributes to protein misfolding and aggregation has still to be elucidated.
We show that the mobility of solvation shell H2O molecules influences the aggregation rate of the amyloid protein α-synuclein (αSyn), a protein associated with Parkinson’s disease. When the mobility of H2O within the solvation shell is reduced by the presence of NaCl, αSyn aggregation rate increases.
Conversely, in the presence CsI the mobility of the solvation shell is increased and αSyn aggregation is reduced. Changing the solvent from H2O to D2O leads to increased aggregation rates, indicating a solvent driven effect.
We show the increased aggregation rate is not directly due to a change in the structural conformations of αSyn, it is also influenced by a reduction in both the H2O mobility and αSyn mobility.
We propose that reduced mobility of αSyn contributes to increased aggregation by promoting intermolecular interactions.
In water droplets like those on early Earth, amino acids can assemble spontaneously into proteins
One of the really tough conundrums about how life got started on Earth is the “water paradox”: Liquid water is necessary for life as we know it here on Earth, and yet a lot of chainlike molecules that all living things need (like proteins, RNA, and DNA) cannot link up spontaneously in liquid water.
Let’s consider proteins. Living organisms can’t make proteins without the help of … already-existing proteins. So how could proteins possibly have arisen in reasonable amounts to help set up the beginning of life on Earth, somewhere between 4.4 and 3.8 billion years ago?
Well, it just got a whole lot easier to explain. A research team at Purdue University led by chemistry professor R. Graham Cooks used a simple but clever setup to convincingly solve this conundrum and show how this could have happened — quite easily, actually — on the early Earth. Their findings were reported October 3 in the Proceedings of the National Academy of Sciences. (Behind a paywall, but I thank Dr. Cooks for kindly sending me a reprint so I could check it out.)
We’re confident that amino acids — the building blocks of proteins — were available on the early Earth because of a bunch of observations:
- Stanley Miller’s famous 1953 experiment ran early-Earth gases methane, ammonia, hydrogen, and water vapor past an electrical discharge (sort of like lightning) in circulation for several days, and plentiful organic compounds were formed, among them aspartate, alanine, glycine, and probably other amino acids.
- In 2018, more-complex amino acids that appear to have formed in the absence of any life were found deep beneath the seafloor in mantle-derived rocks.
- We’ve also seen at least 80 different kinds of amino acids show up in meteorites now.
But protein formation? Not so much. There was one report in 2020 of the first protein being found in a meteorite, which generated some buzz but ultimately didn’t survive peer review and hasn’t appeared in any journal. If it had, believe me, I’d have been all over that one.
So we’ve been looking very hard for a demonstration of how proteins could have formed from amino acids somehow on the early Earth, but until now, no such luck.
Why is it so hard to make proteins out of amino acids in water?
In order to get started, a “condensation” reaction has to occur; that is, two amino acids need to link together and kick out a water molecule:
The two molecules on the left side are both the same kind of molecule: a generic amino acid. All amino acids look like this, the only difference among them being the “R”. “R” can be lots of different things, but life on Earth, with rare exceptions, only uses 20 specific things for “R”.
To link two amino acids together, the “amino” (—NH2) end of one amino acid reacts with the “acid” (—COOH) end of another one. This gives us OC—NH (the “peptide bond”, shown in red on the right above), and it also produces a water molecule (HOH, in blue). But keep in mind that this reaction can also go backwards. And within a body of water, this backward reaction happens way, way, way more often than the forward, just because there’s so dang much water around.
I wanted to find out exactly how obnoxiously difficult it is to make a peptide bond in water, so I used a couple of online tools called eQuilibrator and Calistry to help me out. Let’s take the simplest amino acid — glycine — where the “R” is just a hydrogen (H) and try to link two of them together. Under garden-variety conditions (for those keeping score at home: pH 7.5, 25°C, and 0.25 M salt), it turns out that when this reaction settles to its final equilibrium state, only two out of every 360 quadrillion glycine molecules will have paired up. Sheesh, we’re never going to get life started this way.
As if things weren’t already hard enough, amino acids spend most of their time in the “zwitterionic” form at most pH levels you’d encounter on Earth, where they can’t even react with each other:
This means that even the super-crappy equilibrium state mentioned above will take a really long time to reach. Now you see what an uber-tough nut the “water paradox” is to crack.
So people have concocted explanations to get around this problem in ways that would fit in with conditions on early Earth, proposing that amino acids could be coerced to link together in water under very special circumstances like near natural mineral or clay catalysts, special salts, etc. But these things start to feel like reaches and don’t provide intuitively satisfying answers.
Intelligent-design people would be happy to hear me say that, I suppose, but now I have to burst their bubble.
Cooks’ group provided the part we’d been missing all along — small water droplets — and showed that linking amino acids together within them turns out not to be hard at all. They made a dilute solution of glycine or alanine in water. After two hours, nothing had happened, of course. But when they made fine spray out of those very same solutions, glycine-glycine (Gly-Gly) or alanine-alanine (Ala-Ala) dipeptides formed in easily detectable amounts in a matter of milliseconds.
Their first crack at making the droplets was with nano-electrospray ionization, or nESI. Here we suck electrons out of a liquid (a dilute solution of glycine in water, in this case) by applying a strong voltage between the emitter and the detector. The liquid takes on a net positive charge, so it’s literally pulled over to the negatively charged detector plate as a mist:
The drops get even smaller on their way over to the detector because the positive charges within them repel each other, and this makes the droplets break up. Normally, nESI makes droplets that start out around 0.2 μm (millionths of a meter) wide and get smaller from there.
But now you might say, isn’t putting a charge onto the molecules kind of cheating, though? That doesn’t routinely happen in nature! And if you say that, you are right. It’s not exactly fair. Lots of people have made peptide bonds under crazy, non-Earth-like conditions. Big deal.
So then they repeated the experiment without applying any voltage at all, making the spray by physically pushing the liquid through the emitter with a syringe. The droplets weren’t quite as small, but it worked anyway. The net charge hadn’t been responsible for the effect after all; it was all about the droplets.
But it gets better. They sprayed two glycine-containing mists together and ended up with not only Gly-Gly but also Gly-Gly-Gly and Gly-Gly-Gly-Gly. When they sprayed two jets containg Gly-Gly together, they got Gly-Gly-Gly-Gly and Gly-Gly-Gly-Gly-Gly-Gly! They mixed glycine and alanine sprays together and got mixed peptides like Gly-Gly-Ala, Ala-Gly-Ala, etc.
Hey, this is getting protein-like!
Presumably if you keep slamming peptide-containing droplets together, as in sea spray, waterfall mist, and the like, the peptides can keep getting longer and longer and give you some primitive protein material to work with.
But wait a second. How could these reactions work so fast in little droplets of water but not at all in bulk water? I mean, water is water, isn’t it? The trick seems to be that they happen only at the surface of each droplet. One side of that surface is all water, true, but the other side is air, with very little water. It becomes a whole lot easier to make water — that is, to run a condensation reaction like
Gly + Gly → Gly-Gly + H2O
— when there is no water around. On the surface of a droplet, these molecules can stay dissolved in water and yet have access to a place with no water. And there, my friends, is your solution to the “water paradox”.
There are plenty of other reasons that reactions can behave very differently at an air-water interface, and I mention that because this is actually a pretty hot topic in chemistry now. It’s known that the —OH groups of water molecules can stick up at the surface, not being part of the (weak) bonding network they would have within the liquid, and that alone provides a different environment:
There’s even an electric field across the air-water interface, and while that isn’t at all well-understood, it certainly can influence chemical reactions quite a bit.
The Purdue researchers observed that smaller droplets are better, because smaller droplets have a higher surface-to-volume ratio, so that means more surface area to do reactions compared to the volume to be filled, and so products like Gly-Gly can get more concentrated and be easier to detect.
Can water droplets in nature get so tiny? Of course they can! Any droplet suspended in air will evaporate completely over time, so within a spray or mist we can generally have a full range of droplet sizes at any one time.
It should be pointed out that, incredibly enough, the total surface area of sea spray on Earth is actually larger than the planet’s entire air-sea interface! Not to mention all the droplets in clouds, waterfalls, rapids, etc. So this is a hugely significant venue for new classes of chemical reactions occurring in nature, many of which we probably don’t even know about yet.
The same principle that applies to proteins here could very well also apply to DNA, RNA, polysaccharides, phosphates, and anything else biologically important that forms by condensation. Hopefully our Purdue team will give some of those things a try next!
But for now, one more unfathomable step in the emergence of life on Earth just got a whole lot more fathomable. It’s always mesmerizing to watch the waves crash on the shore, and maybe part of the reason why is that we’re looking at the very beginnings of where we came from.
Shocking Study Finds Decreased Proteins – Not Amyloid Plaques – Cause Alzheimer’s Disease
The prevailing theory is that Alzheimer’s disease is caused by the buildup of amyloid plaques in the brain. However, new research finds that it is actually caused by a decline in levels of a specific protein.
New research on patients with mutations published in the Journal of
UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the research on October 4, 2022, in the Journal of Alzheimer’s Disease.
Questioning the dominant hypothesis
This research study was focused on a protein called amyloid-beta. The protein normally carries out its functions in the brain in a form that is soluble, meaning that it is dissolvable in water. However, it sometimes hardens into clumps, known as amyloid plaques.
“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic. When done, patients have gotten worse.” — Andrea Sturchio, MD
For more than 100 years, the conventional wisdom in the field of Alzheimer’s research stated that Alzheimer’s was caused by the buildup of amyloid plaques in the brain. However, Espay and his colleagues hypothesized that plaques are actually just a consequence of the levels of soluble amyloid-beta in the brain decreasing. These levels decrease because the normal protein, under situations of biological, metabolic, or infectious stress, transforms into the abnormal amyloid plaques.
“The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia,” said Espay. He is a a UC Health physician, a professor of neurology in the UC College of Medicine, and director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.”
Alberto Espay, MD, MSc, professor of neurology at the UC College of Medicine and Director and Endowed Chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders. Credit: Colleen Kelley/UC Brand + Creative
Sturchio noted that over the years many clinical trials and research studies have aimed at reducing amyloid plaques in the brain. Some have succeeded in lessening plaques, but until the September 27 announcement of a positive trial by Biogen and Eisai (lecanemab), none actually slowed the progression of Alzheimer’s disease. More importantly, in support of their hypothesis, in some of the clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.
“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic,” said Sturchio. He is the first author of the report and an adjunct research instructor at UC’s College of Medicine. “When done, patients have gotten worse.”
Research results
Previous research from the team found that regardless of the buildup of plaques in the brain, people with high levels of soluble amyloid-beta were cognitively normal, but those with low levels of the protein were more likely to have cognitive impairment.
Andrea Sturchio, MD. Credit: Provided
In the current study, the research team examined the levels of amyloid-beta in a subset of patients with mutations that predict an overexpression of amyloid plaques in the brain, which is thought to make them more likely to develop Alzheimer’s disease.
“One of the strongest supports to the hypothesis of amyloid toxicity was based on these mutations,” Sturchio said. “We studied that population because it offers the most important data.”
Even in this group of patients thought to have the highest risk of Alzheimer’s disease, the scientists observed similar results as the study of the general population.
“What we found was that individuals already accumulating plaques in their brains who are able to generate high levels of soluble amyloid-beta have a lower risk of evolving into dementia over a three-year span,” Espay said.
The research found that people can remain cognitively normal regardless of the amount of amyloid plaques in their brains as long as they maintain a baseline level of soluble amyloid-beta in the brain above 270 picograms per milliliter.
“It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques,” Espay said. “Degeneration is a process of loss, and what we lose turns out to be much more important.”
Next steps
According to Sturchio, the research is moving forward to investigate whether increasing the levels of soluble amyloid-beta in the brain is a beneficial therapy for patients with Alzheimer’s.
Espay said it will be essential to ensure that the elevated levels of the protein introduced into the brain do not then turn into amyloid plaques, since the soluble version of the protein is needed for normal function to make an impact in the brain.
On a larger scale, the research team believes a similar hypothesis of what causes neurodegeneration can be applied to other diseases including Parkinson’s and Creutzfeldt-Jakob disease. Research is ongoing in these areas as well.
For instance, in Parkinson’s disease, a normal soluble protein in the brain called alpha-synuclein can harden into a deposit called a Lewy body. The researchers hypothesize that Parkinson’s is not caused by Lewy bodies aggregating in the brain, but instead by a decrease in levels of normal, soluble alpha-synuclein.
“We’re advocating that what may be more meaningful across all degenerative diseases is the loss of normal proteins rather than the measurable fraction of abnormal proteins,” Espay said. “The net effect is a loss not a gain of proteins as the brain continues to shrink as these diseases progress.”
Espay said he envisions a future with two approaches to treating neurodegenerative diseases: rescue medicine and precision medicine.
Rescue medicine looks like the current work, examining whether boosting levels of key proteins like amyloid-beta leads to better outcomes.
“Interestingly, lecanemab, the anti-amyloid drug recently reported as beneficial, does something that most other anti-amyloid treatments don’t do in addition to reducing amyloid: it increases the levels of the soluble amyloid-beta,” Espay said.
Alternatively, precision medicine entails going deeper to understand what is causing levels of soluble amyloid-beta to decrease in the first place, whether it is a virus, toxin, nanoparticle, or biological or genetic process. If the root cause is addressed, the levels of the protein wouldn’t need to be boosted because there would be no transformation from soluble, normal proteins to amyloid plaques.
Espay said precision medicine would provide more personalized treatments by taking into account the fact that no two patients are exactly alike. The researchers are making progress in precision medicine through the Cincinnati Cohort Biomarker Program, a project aiming to divide neurodegenerative diseases by biological subtypes in order to match therapies based on biomarkers to those most likely to benefit from them.
“The Cincinnati Cohort Biomarker Program is dedicated to working toward deploying the first success in precision medicine in this decade,” Espay said. “By recognizing biological, infectious and toxic subtypes of Parkinson’s and Alzheimer’s, we will have specific treatments that can slow the progression of those affected.”
Reference: “High Soluble Amyloid-ß42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations” by Andrea Sturchio, Alok K. Dwivedi, Tarja Malm, Matthew J.A. Wood, Roberto Cilia, Jennifer S. Sharma, Emily J. Hill, Lon S. Schneider,Neill R. Graff-Radford, Hiroshi Mori, Georg Nübling, Samir El Andaloussi, Per Svenningsson, Kariem Ezzat, Alberto J. Espay and the Dominantly Inherited Alzheimer Consortia (DIAN), 16 September 2022, Journal of Alzheimer’s Disease.
DOI: 10.3233/JAD-220808
Study: Decreased proteins, not amyloid plaque
image: Alberto Espay, MD
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Credit: Photo/Colleen Kelley/UC Marketing + Brand
New research from the University of Cincinnati bolsters a hypothesis that Alzheimer’s disease is caused by a decline in levels of a specific protein, contrary to a prevailing theory that has been recently called into question.
UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the research on Oct. 4 in the Journal of Alzheimer’s Disease.
Questioning the dominant hypothesis
The research is focused on a protein called amyloid-beta. The protein normally carries out its functions in the brain in a form that is soluble, meaning dissolvable in water, but it sometimes hardens into clumps, known as amyloid plaques.
The conventional wisdom in the field of Alzheimer’s research for more than 100 years stated that Alzheimer’s was caused by the buildup of amyloid plaques in the brain. But Espay and his colleagues hypothesized that plaques are simply a consequence of the levels of soluble amyloid-beta in the brain decreasing. These levels decrease because the normal protein, under situations of biological, metabolic or infectious stress, transform into the abnormal amyloid plaques.
“The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia,” said Espay, professor of neurology in the UC College of Medicine, director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute and a UC Health physician. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.”
Sturchio noted that many research studies and clinical trials over the years have aimed at reducing amyloid plaques in the brain, and some have lessened plaques, but until the September 27 announcement of a positive trial by Biogen and Eisai (lecanemab), none slowed the progression of Alzheimer’s disease. More importantly, in support of their hypothesis, in some clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.
“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic,” said Sturchio, first author of the report and adjunct research instructor at UC’s College of Medicine. “When done, patients have gotten worse.”
Research results
Previous research from the team found that regardless of the buildup of plaques in the brain, people with high levels of soluble amyloid-beta were cognitively normal, while those with low levels of the protein were more likely to have cognitive impairment.
In the current study, the team analyzed the levels of amyloid-beta in a subset of patients with mutations that predict an overexpression of amyloid plaques in the brain, which is thought to make them more likely to develop Alzheimer’s disease.
“One of the strongest supports to the hypothesis of amyloid toxicity was based on these mutations,” Sturchio said. “We studied that population because it offers the most important data.”
Even in this group of patients thought to have the highest risk of Alzheimer’s disease, the researchers found similar results as the study of the general population.
“What we found was that individuals already accumulating plaques in their brains who are able to generate high levels of soluble amyloid-beta have a lower risk of evolving into dementia over a three-year span,” Espay said.
The research found that with a baseline level of soluble amyloid-beta in the brain above 270 picograms per milliliter, people can remain cognitively normal regardless of the amount of amyloid plaques in their brains.
“It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques,” Espay said. “Degeneration is a process of loss, and what we lose turns out to be much more important.”
Next steps
Sturchio said the research is moving forward to study if increasing the levels of soluble amyloid-beta in the brain is a beneficial therapy for patients with Alzheimer’s.
Espay said it will be important to ensure that the elevated levels of the protein introduced into the brain do not then turn into amyloid plaques, since the soluble version of the protein is needed for normal function to make an impact in the brain.
On a larger scale, the researchers said they believe a similar hypothesis of what causes neurodegeneration can be applied to other diseases including Parkinson’s and Creutzfeldt-Jakob disease, with research ongoing in these areas as well.
For example, in Parkinson’s disease, a normal soluble protein in the brain called alpha-synuclein can harden into a deposit called a Lewy body. The researchers hypothesize that Parkinson’s is not caused by Lewy bodies aggregating in the brain, but rather by a decrease in levels of normal, soluble alpha-synuclein.
“We’re advocating that what may be more meaningful across all degenerative diseases is the loss of normal proteins rather than the measurable fraction of abnormal proteins,” Espay said. “The net effect is a loss not a gain of proteins as the brain continues to shrink as these diseases progress.”
Espay said he envisions a future with two approaches to treating neurodegenerative diseases: rescue medicine and precision medicine.
Rescue medicine looks like the current work, studying if boosting levels of key proteins like amyloid-beta leads to better outcomes.
“Interestingly, lecanemab, the anti-amyloid drug recently reported as beneficial, does something that most other anti-amyloid treatments don’t do in addition to reducing amyloid: it increases the levels of the soluble amyloid-beta,” Espay said.
Alternatively, precision medicine entails going deeper to understand what is causing levels of soluble amyloid-beta to decrease in the first place, whether it is a virus, a toxin, a nanoparticle or a biological or genetic process. If the root cause is addressed, the levels of the protein wouldn’t need to be boosted because there would be no transformation from soluble, normal proteins to amyloid plaques.
Espay said precision medicine would take into account the fact that no two patients are alike, providing more personalized treatments. The researchers are making progress in precision medicine through the Cincinnati Cohort Biomarker Program, a project aiming to divide neurodegenerative diseases by biological subtypes in order to match therapies based on biomarkers to those most likely to benefit from them.
“The Cincinnati Cohort Biomarker Program is dedicated to working toward deploying the first success in precision medicine in this decade,” Espay said. “By recognizing biological, infectious and toxic subtypes of Parkinson’s and Alzheimer’s, we will have specific treatments that can slow the progression of those affected.”
Journal
Journal of Alzheimer s Disease
Method of Research
Observational study
Subject of Research
People
Article Title
High Soluble Amyloid-Beta42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations
Article Publication Date
4-Oct-2022