Publisher Health

Like other factors such as age, sex and genetics, smoking has a major impact on immune responses. This is the finding recently made by a team of scientists at the Institut Pasteur using the Milieu Intérieur cohort of 1,000 healthy volunteers, established to understand variability in immune responses. In addition to its short-term impact on immunity, smoking also has long-term consequences. For many years after they have quit the habit, smokers are left with effects on some of their bodies’ defense mechanisms acquired while smoking. These findings, which for the first time reveal a long-term memory of the effects of smoking on immunity, will be published in the journal Nature on February 14, 2024.
Individuals’ immune systems vary significantly in terms of how effectively they respond to microbial attacks. But how can this variability be explained? What factors cause these differences? “To answer this key question, we set up the Milieu Intérieur cohort comprising 1,000 healthy individuals aged 20 to 70 in 2011,” comments Darragh Duffy, Head of the Translational Immunology Unit at the Institut Pasteur and last author of the study. While certain factors such as age, sex and genetics are known to have a significant impact on the immune system, the aim of this new study was to identify which other factors had the most influence.”
The scientists exposed blood samples taken from individuals in the Milieu Intérieur cohort to a wide variety of microbes (viruses, bacteria, etc.) and observed their immune response by measuring levels of secreted cytokines(1). Using the large quantities of data gathered for individuals in the cohort, the team then determined which of the 136 investigated variables (body mass index, smoking, number of hours’ sleep, exercise, childhood illnesses, vaccinations, living environment, etc.) had the most influence on the immune responses studied. Three variables stood out: smoking, latent cytomegalovirus infection(2) and body mass index. “The influence of these three factors on certain immune responses could be equal to that of age, sex or genetics,” points out Darragh Duffy.
As regards smoking, an analysis of the data showed that the inflammatory response, which is immediately triggered by infection with a pathogen, was heightened in smokers, and moreover, the activity of certain cells involved in immune memory was impaired. In other words, this study shows that smoking disrupts not only innate immune mechanisms, but also some adaptive immune mechanisms. “A comparison of immune responses in smokers and ex-smokers revealed that the inflammatory response returned to normal levels quickly after smoking cessation, while the impact on adaptive immunity persisted for 10 to 15 years,” observes Darragh Duffy. “This is the first time it has been possible to demonstrate the long-term influence of smoking on immune responses.”
Basically, the immune system appears to have something resembling a long-term memory of the effects of smoking. But how? “When we realized that the profiles of smokers and ex-smokers were similar, we immediately suspected that epigenetic processes were at play(3),” says Violaine Saint-André, a bioinformatician in the Institut Pasteur’s Translational Immunology Unit and first author of the study. “We demonstrated that the long-term effects of smoking on immune responses were linked to differences in DNA methylation(4) — with the potential to modify the expression of genes involved in immune cell metabolism — between smokers, ex-smokers and non-smokers.” It therefore appears that smoking can induce persistent changes to the immune system through epigenetic mechanisms.
“This is a major discovery elucidating the impact of smoking on healthy individuals’ immunity and also, by comparison, on the immunity of individuals suffering from various diseases,” concludes Violaine Saint-André.
Notes:
(1) proteins secreted by a large number of immune cells to communicate among themselves and participate in immune defense.

(2) a virus in the herpes family that is often asymptomatic though dangerous to fetuses.
(3) changes in DNA that affect how genes are expressed, i.e. how they are used by cells.
(4) methylation is a type of chemical modification. Methyl groups position themselves on DNA, changing the way in which the genome is read in the cell.

Doctors and pharmacists seem to be confused by the guidelines. And the brand names aren’t helping.This winter, for the first time ever, there were two vaccines available to ward off respiratory syncytial virus, which is particularly dangerous to older adults and infants. Only one of them — Abrysvo, made by Pfizer — was approved for pregnant women, and neither was for young children.The distinction apparently slipped by some clinicians and pharmacists.At least 128 pregnant women were mistakenly given the alternative vaccine — Arexvy, by GSK — and at least 25 children under age 2 received a vaccination, the Centers for Disease Control and Prevention has warned. Dr. Sarah Long, a pediatric infectious disease physician and an adviser to the agency, said she was “blindsided” by the reports. “It is very upsetting that this should happen,” she said.Arexvy has not been tested in pregnant women or children, so information about its effects in those groups is limited. No serious harms from the errors have yet been confirmed, but the outcome was unknown in a majority of reported cases.Based on available data, Dr. Long said she was more concerned about the young children who received an R.S.V. vaccine than the pregnant women who received Arexvy or their babies. Evidence from animal testing “strongly suggests” that Arexvy might exacerbate R.S.V. infection in children younger than 2, rather than mitigate it, according to the Food and Drug Administration.To prevent that, the C.D.C. has recommended that the children who mistakenly got either vaccine also be given nirsevimab (sold as Beyfortus), a monoclonal antibody that provides strong immune protection, while the R.S.V. season lasts.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Published26 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Yonsei UniversityBy Michelle RobertsDigital health editorScientists have created a new type of hybrid food – a “meaty” rice that they say could offer an affordable and eco-friendly source of protein.The porous grains are packed with beef muscle and fat cells, grown in the lab. The rice was first coated in fish gelatine to help the beef cells latch on, and the grains were left in a petri dish to culture for up to 11 days. The researchers say the food may serve as “relief for famine, military ration, or even space food” in the future. It remains to be seen whether consumers would take to it if it gets to market.The hybrid rice is apparently a bit firmer and brittler than regular rice, but packs more protein, Matter journal reports.According to the team at Yonsei University in South Korea, it has 8% more protein and 7% more fat.And, compared to regular beef, it has a smaller carbon footprint, since the production method eliminates the need to raise and farm lots of animals.For every 100g (3.5oz) of protein produced, hybrid rice is estimated to release under 6.27kg (13.8lb) of carbon dioxide, while beef production releases eight times more at 49.89kg, they say. Researcher Sohyeon Park explained: “We usually obtain the protein we need from livestock, but livestock production consumes a lot of resources and water and releases a lot of greenhouse gas.”Imagine obtaining all the nutrients we need from cell-cultured protein rice.”Rice already has a high nutrient level, but adding cells from livestock can further boost it.”She said: “I didn’t expect the cells to grow so well in the rice. Now I see a world of possibilities for this grain-based hybrid food.”‘People need convincing’Rice appears to provide a scaffold or structure for the meat cells to grow in, and also gives them nutrients.The team is not the first to explore lab-grown or cultivated meat products. Since the first lab-grown burger was unveiled in London in 2013, dozens of companies around the world have joined the race to bring affordable cultivated meat to the market.Singapore recently started selling the world’s first cultivated chicken product to customers. Meanwhile, Italy has backed a bill to ban laboratory-produced meat in order to safeguard the country’s food traditions.Critics point out there is nothing synthetic about lab-grown meat – it is made by growing natural cells.Prof Neil Ward, an agri-food and climate specialist at the University of East Anglia, said this type of research holds promise for the development of healthier and more climate-friendly diets in future, but that some people needed convincing.”While data on cost and climate impact look very positive, a critical test is around public appetite for these sorts of lab-developed foods,” he said. “With lab-based alternative meats in general, the greatest potential is probably in replacing processed meats rather than prime cuts.”Bridget Benelam from the British Nutrition Foundation said: “Developing a diet that supports health for both people and planet is a major challenge. This study demonstrates an innovative new approach that could contribute to the solution.”But she added: “The findings represent a relatively small increase in the protein content of rice, which isn’t a high protein food. So further work would be needed if this technology were to be used as an alternative protein source to traditional animal products.More on this storyThe only place in the world selling lab-grown meatPublished8 June 2023Lab-grown chicken safe to eat, say US regulatorsPublished17 November 2022Lab-grown meat may have climate costPublished19 February 2019Around the BBCWhy cultivated meat is still so hard to find – BBC Future

Published2 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Annabel RackhamBBC NewsUltra-processed foods should be clearly labelled, experts say.Scientists said the warnings were needed as some ultra-processed foods could fall into the “healthy” green category of the “traffic-light” system.This was the case for meat-alternative products, the University College London team said, and some people may be unaware what they were buying was ultra-processed.Ultra-processed foods have been linked to obesity and heart disease.Five ingredientsCurrently, labels must show whether a food item is high in fat, salt and sugar but reveal no information about how processed it is.UPFs are defined by how they are made and what they contain.They often have more than five ingredients, with examples including cakes, biscuits and yoghurts.At the other end of the scale are unprocessed foods such as fruits, vegetables and fresh meat – and in the middle, processed foods such as cheeses, tinned products and some bread.Image source, Getty ImagesOf nearly 3,000 food and drink items popular in the UK the researchers looked at:55% were ultra-processed and labelled red, containing significantly more fat, saturated fat, sugar, salt and energy per 100g than the minimally or unprocessed, which tended to be labelled greenBut some UPFs were green and some minimally processed, such as nuts, seeds and whole milk, redImage source, Getty ImagesUCL senior research fellow and weight-management specialist Dr Adrian Brown told BBC News he had looked at a “meat alternative”, for example.”Generally, it can be considered highly processed – but if you look at front-of-package labelling for energy, fat, saturated fat and sugar, they’re all green, which would be considered healthy,” he said.Could ultra-processed foods be harmful for us?Ultra-processed foods ‘make you eat more’And there was too little research into the effect of UPFs on general health.”There’s a bit of a grey area [with UPFs] as, at this present time, we only have association data between ultra-processed food and health outcomes such as diabetes and heart disease,” Dr Brown said.Image source, Getty ImagesThe government’s Scientific Advisory Committee on Nutrition (SACN) also described “uncertainties around the quality of evidence available”.Dr Brown’s team at UCL have now begun a trial to see how healthy a UFP-only diet can be, compared with a minimally processed one, and whether guidance should be given to consumers.”We’re putting people on an eight-week diet which meets the government’s recommendations for salt, fat, sugar and energy – what is considered healthy – and we’re comparing the outcomes of them, related to weight and other changes in terms of health as well,” he said.More on this storyCould ultra-processed foods be harmful for us?Published5 June 2023Ultra-processed foods ‘make you eat more’Published16 May 2019UN climate talks take aim at planet-warming foodPublished1 December 2023

A drug used to treat rheumatoid arthritis could also prevent the disease in individuals deemed to be at risk.
Results from a Phase 2b clinical trial, published today in The Lancet by researchers led by King’s College London, provides hope for arthritis sufferers after it was shown that the biologic drug abatacept reduces progression to this agonising chronic inflammatory disease.
Rheumatoid arthritis affects half a million people in the UK and develops when the body’s immune system attacks itself, causing joint pain, swelling and significant disability. The disease most commonly begins in middle age, but much younger age groups can be afflicted, and until now there is no cure or prevention.
Abatacept is currently used as an effective second or third line treatment for people living with established rheumatoid arthritis and is given by weekly injections at home or in hospital via a drip.
Researchers from King’s College London recruited 213 patients at high risk of the disease to understand whether a year-long treatment of the biologic drug could be used to prevent progression to rheumatoid arthritis.
They recruited men and women over the age of 18 with early symptoms such as joint pain but no joint swelling, and treated half with the drug and half with a placebo every week for a year. The study drug was then stopped, and study participants monitored for a further 12 months.
After twelve months of treatment, 6% of patients treated with abatacept had developed arthritis compared to 29% in the placebo arm. By 24 months, the differences were still significant, with a total of 25% progressing to rheumatoid arthritis in the abatacept arm compared to 37% in the placebo arm.

Professor Andrew Cope, from King’s College London, said: “This is the largest rheumatoid arthritis prevention trial to date and the first to show that a therapy licensed for use in treating established rheumatoid arthritis is also effective in preventing the onset of disease in people at risk. These initial results could be good news for people at risk of arthritis as we show that the drug not only prevents disease onset during the treatment phase but can also ease symptoms such as pain and fatigue. This is also promising news for the NHS as the disease affects people as they age and will become more expensive to treat with a growing aging population.”
Secondary outcomes for the trial showed that abatacept was associated with improvements in pain scores, function and quality of life measurements, as well as lower scores of inflammation of the lining of joints detectable by ultrasound scan.
Philip Day, a 35-year-old software engineer and founder of FootballMatcher from Eltham, was at high-risk for rheumatoid arthritis. A keen football player, Philip’s joint pain deterred him from playing and affected his day-to-day life. He was enrolled in the trial in 2018, at the age of the 30, and was prescribed abatacept.
He said: “The pain got so terrible I stopped going to football, and I got lazier and felt progressively worse physically and mentally. The pain was unpredictable, it would show up in my knees one day, my elbows the next, and then my wrists or even my neck. At the time, my wife and I wanted to have children and I realised my future was pretty bleak if the disease progressed. I’d always wanted to be the kind of dad that played football with his son and I knew the pain would stop me from realising that dream.
“Enrolling in the trial was a no-brainer; it was a ray of hope at a dark time. Within a few months I had no more aches or pains and five years on I’d say I’ve been cured. Now, I can play football with my three-year-old son and have a normal life.”
One year’s treatment with abatacept costs the NHS about £10,000 per patient and is not without risk. Side effects include upper respiratory tract infections, dizziness, nausea and diarrhea, but these are generally mild.

Professor Cope added: “There are currently no drugs available that prevent this potentially crippling disease. Our next steps are to understand people at risk in more detail so that we can be absolutely sure that those at highest risk of developing rheumatoid arthritis receive the drug.”
Rheumatologist Professor Sir Ravinder N Maini FRS FMedSci FRCP, who was not involved in the research, said: “Professor Cope and colleagues from King’s College, London, in collaboration with researchers in the UK and Netherlands, have published the results of an exciting clinical trial in The Lancet, which demonstrates that it is now possible to prevent the onset of RA, a disease that remains incurable despite great advances in its treatment in the recent past.
“The results clearly show that during the treatment period almost all individuals receiving the biologic drug showed no symptoms or signs of RA compared with the control population amongst many more developed RA. In the follow up period of 1 year off treatment, it is interesting to note that some appeared to go into remission.
“Prevention of disease is of course a highly desirable goal in preventing the ravages of disabling RA, which is associated with a significant social and financial burden. Many further questions arise from this important study. For example, will this preventive approach be safe and cost effective if continued long term or can the selection of suitable populations be refined so that only those likely to benefit most are treated with a short course of treatment?”

A former gas station owner, he was learning to read the Bible in its original languages when he changed course and started what became an artisanal-grains powerhouse.Bob Moore, the grandfatherly entrepreneur who, with his wife, Charlee, leveraged an image of organic heartiness and wholesome Americana to turn the artisanal grain company Bob’s Red Mill into a $100 million dollar-a-year business, died on Saturday at his home in Milwaukie, Ore. He was 94.His death was announced by the company, which did not cite a cause.Founded in Milwaukie in 1978, Bob’s Red Mill grew from serving the Portland area to become a global natural-foods behemoth, marketing more than 200 products in more than 70 countries. The company’s product line runs a whole-grain gamut, including stone-ground sorghum flour, paleo-style muesli and whole wheat-pearl couscous, along with energy bars and cake and soup mixes.Over the years, the company profited handsomely from the nutrition-minded shift away from processed foods and grains.“I think that people who eat white flour, white rice, de-germinated corn — in other words, grains that have had part of their nutrients taken away — are coming up short,” Mr. Moore said in 2017 in an interview for an Oregon State University oral history. “I think our diets, nationally, and international probably, show the fact that we just have allowed ourselves to be sold a bill of goods.”Despite the company’s explosive growth, Mr. Moore fended off numerous offers by food giants to buy Bob’s Red Mill. He opted instead for an employee stock ownership plan, instituted in 2010, on his 81st birthday; by April 2020, the plan had put 100 percent of the company in the hands of its more than 700 employees.“The Bible says to do unto others as you would have them do unto you,” Mr. Moore, an observant Christian, said in discussing the plan in a recent interview with Portland Monthly magazine.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Alaska state health officials said that a man died last month of the virus, which occurs mostly in small mammals and causes lesions. There have been seven reported human cases since 2015.An Alaska man died last month of Alaskapox, a rare virus that occurs mostly in small mammals and can cause skin lesions, according to state health officials.Alaskapox was first identified in 2015 in a woman who lived near Fairbanks, Alaska, and there have been a total of seven cases of the virus reported to the Alaska Section of Epidemiology. Until last month, no one had been hospitalized or died of Alaskapox, which can also cause swollen lymph nodes and muscle or joint pain, Alaska epidemiology officials said on Friday.Of the seven people who have had Alaskapox, six lived in the Fairbanks North Star Borough, where red-backed voles and shrews have been found to have the virus, according to the Alaska Department of Health. Alaskapox has not been found to spread between humans.Dr. Julia Rogers, an epidemiologist with the Centers for Disease Control and Prevention, said in an interview on Tuesday that the symptoms from Alaskapox infection were generally mild.“There could have been cases in the past that we just did not pick up because of that,” Dr. Rogers said, adding that it is possible that recorded cases could increase as more doctors learn how to identify it.The Alaska Section of Epidemiology, which did not release the name of the man who died of the virus, said in a statement that he was “an elderly man from the Kenai Peninsula with a history of drug-induced immunosuppression.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Living organisms often create what is needed for life from scratch.
For humans, this process means the creation of most essential compounds needed to survive. But not every living thing has this capability, such as the parasite that causes malaria, which affected an estimated 249 million people in 2022.
Virginia Tech researchers in the College of Agriculture and Life Sciences found that by preventing the malaria parasite from scavenging fatty acids, a type of required nutrient, it could no longer grow.
“The key to this breakthrough is that we were able to develop a screening method for the malaria parasite and block this process,” said Michael Klemba, associate professor of biochemistry and principal investigator on the project. “While very much in its infancy, the results could open the door to a new way to fight malaria.”
Malaria is caused while the parasite is replicating in human red blood cell and it relies on scavenging, rather than creating, to satisfy its need for fatty acids. Many fatty acids are obtained by metabolizing a class of host lipid, called lysophospholipids. However, scientists didn’t know how the parasite releases fatty acids from the host lipids.
The Virginia Tech research team did experiments with infected red blood cells and found chemicals that can stop the parasite from getting the needed fatty acids. Researchers discovered that two enzymes were instrumental in breaking down host lipids to release the fatty acids the parasite needs. These enzymes work in different places: One works outside in the red blood cell, and the other works inside the parasite.
When scientists removed these two enzymes, they found that the parasite struggled to get the needed fatty acids and couldn’t grow well. This was especially true when that host lipid was the only fatty acid source available. When both enzymes were stopped from working, either by changing the parasite’s genes or by using drugs, the parasites couldn’t grow in human blood.

This shows that breaking down the host lipid, called lysophosphatidylcholine, to get fatty acids is critical for the malaria parasite’s survival in our bodies and that targeting these two enzymes could be a new way to fight malaria.
The research was published today by Proceedings of the National Academy of Sciences of the United States of America and was funded by a National Institutes of Health grant, United States Department of Agriculture Hatch funding, and through the Department of Biochemistry at Virginia Tech.
Laying the groundwork
In 2017, a study came out that showed when lysophosphatidic acid levels drop in the host that the malaria parasite, known as Plasmodium falciparum, converts into a form that can be taken up by mosquitoes. P. falciparum causes malaria while replicating in host erythrocytes, or red blood cells, and relies on scavenging rather than synthesis, or the creation of compounds, to satisfy its need for fatty acids.
This seemed to be an important environmental cue, Klemba said, and that there was also evidence that host lipids were a preferred source of fatty acids.
“There wasn’t clarity on what the metabolic pathways were,” he said. “If we could show that that these metabolic pathways were useful, then that would be an important contribution to the field.”
For Klemba, this was an important question to answer and one that his lab — and students — were in a unique position to do. Two graduate students worked on the project — Jiapeng Liu ’23, now a postdoctoral scholar at Rutgers University, and Christie Dapper, a former professor at Virginia Tech. Liu was the lead author and Katherine Fike assisted with the project as a research specialist.

“There are two enzymes that are really important for this process: one is inside the parasite, and the other is exported into the host cell,” Klemba said. “Which is not typical of metabolic processes as they are typically carried out within the parasite. Why did the parasite find it useful to put one of these enzymes into the host? We have some ideas that that could be involved in host modification, which could be that the parasite remodels the red cell once it’s once it’s set up shop.”
The researchers found that only removing one of the two enzymes, which they named XL2 and XLH4, doesn’t do anything. Both have to be removed to inhibit parasitic growth.
Future work
There are some limitations of the discovery: The research was conducted only using a culture dish, commonly referred to as in vitro. The researchers also are not sure if the compounds used to inhibit the two enzymes are toxic.
Some level of toxicity is expected, Klemba explained, and it may be possible to engineer the toxicity out of the compounds.
“But that could be a major challenge,” he said.
In the meantime, this discovery could open the door to therapeutic treatments for malaria.

A new study led by researchers at the Marshall University Joan C. Edwards School of Medicine sheds light on the intricate interplay of brain regions involved in nicotine’s effects on the human brain.
The research, published in eNeuro, an open-access, peer-reviewed scientific journal published by the Society for Neuroscience, explores how nicotine influences key areas associated with reward and aversion, showcasing a nuanced relationship that varies based on dosage, sex and distinct brain regions. The medial habenula (MHb), a region known for regulating nicotine aversion, takes center stage in the study. Researchers discovered that MHb activity experiences fluctuations, either heightened or diminished, depending on factors such as the amount of nicotine consumed, dosage variations (with or without menthol), and the sex of the subject. Intriguingly, this modulation was not mirrored in reward centers like the ventral tegmental area, challenging previous assumptions about nicotine’s impact.
“This study demonstrates that the activity of crucial brain regions associated with nicotine dependence is altered in different ways based on nicotine dosage and sex,” said lead researcher Nathan Olszewski, a biomedical research doctoral student at Marshall University in the laboratory of Brandon J. Henderson, Ph.D. “Nicotine usage affects individuals uniquely, making it advisable for users to exercise caution.”
The study employed a vapor-inhalation model of nicotine self-administration in mice, utilizing nose poking to earn nicotine vapor deliveries. Employing patch-clamp electrophysiology, researchers elucidated changes in neuronal excitability in the medial habenula and ventral tegmental area based on nicotine dosage and sex. Fast-scan cyclic voltammetry was also used to assess changes in dopamine release dynamics in the nucleus accumbens.
“In our field, attention has predominantly focused on specific regions like the ventral tegmental area,” said Henderson, an associate professor of biomedical sciences at Marshall University. “This study underscores the necessity of exploring other brain areas controlling the negative aspects of nicotine exposure.”
The researchers aim to expand their investigation to other brain regions, particularly focusing on the interplay between the MHb and the interpeduncular nucleus (IPN). This circuit, known as the aversive pathway of nicotine usage, plays a crucial role in limiting nicotine intake and withdrawal symptoms. Future research will utilize electrophysiology, confocal microscopy and RNA-fluorescent in situ hybridization (FISH) to understand how nicotine alters the activity and expression of nicotinic acetylcholine receptors in this aversive circuit.
In addition to Olszewski and Henderson, Samuel Tetteh-Quarshie, another Ph.D. student in the Henderson laboratory, is a co-author on the study. This study was supported with grant funding (#DA050717 to Henderson) from the National Institute on Drug Abuse (NIDA).

Many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, are characterized by the accumulation of protein clumps, or aggregates, in the brain, which has led scientists to assume that the protein tangles kill brain cells. The search for treatments that break up and remove these tangled proteins has had little success, however.
But a new discovery by University of California, Berkeley, researchers suggests that the accumulation of aggregated proteins isn’t what kills brain cells. Rather, it’s the body’s failure to turn off these cells’ stress response.
In a study published online Jan. 31 in the journal Nature, the researchers reported that delivering a drug that forces the stress response to shut down saves cells that mimic a type of neurodegenerative disease known as early-onset dementia.
According to lead researcher Michael Rapé, the finding could offer clinicians another option for treatment for some neurodegenerative diseases, at least for those caused by mutations in the protein that switches off the cellular stress response. These include inherited diseases that lead to ataxia, or loss of muscle control, and early-onset dementia.
In addition, Rapé noted that other neurodegenerative diseases, including Mohr-Tranebjærg syndrome, childhood ataxia and Leigh syndrome, are also characterized by stress responses in overdrive and have symptoms similar to those of the early onset dementia mimicked in the new study.
“We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells. Yet, we now found that aggregates prevent silencing of a stress response that cells originally mount to cope with bad proteins. The stress response is always on, and that’s what kills the cells,” said Rapé, head of the new division of molecular therapeutics in UC Berkeley’s Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator. “We think that the same mechanisms may underlie more common pathologies that also show widespread aggregation, such as Alzheimer’s disease or frontotemporal dementia, but more work is needed to investigate the role of stress signaling in these diseases.”
Key to the discoveries by Rapé’s lab was the researchers’ finding that stress responses need to be turned off once a brain cell has successfully addressed a difficult situation. Rapé explained this finding to his son in simple terms: You not only need to clean up your room, but also turn out the light before going to bed. If you don’t turn off the light, you can’t fall asleep, but if you turn it off before you cleaned up your room, you would stumble if you had to get up in the dark.

Similarly, a cell has to clean up protein aggregates before turning off the stress response. If it doesn’t turn off the stress response, the cell will ultimately die.
“Aggregates don’t kill cells directly. They kill cells because they keep the light on,” he said. “But that means that you can treat these diseases, or at least the dozen or so neurodegenerative diseases that we found have kept their stress responses on. You treat them with an inhibitor that turns off the light. You don’t have to worry about completely getting rid of large aggregates, which changes how we think about treating neurodegenerative diseases. And most importantly, it makes this really doable.”
In their paper, Rapé and his colleagues describe a very large protein complex they discovered and called SIFI (SIlencing Factor of the Integrated stress response). This machine serves two purposes: It cleans up aggregates and, afterward, turns off the stress response triggered by the aggregated proteins. The stress response controlled by SIFI is switched on to deal with specific intracellular problems — the abnormal accumulation of proteins that end up at the wrong location in the cell. If components of SIFI are mutated, the cell will accumulate protein clumps and experience an active stress response. But it is the stress response signaling that kills the cells.
“The SIFI complex would normally clear out the aggregating proteins. When there are aggregates around, SIFI is diverted from the stress response, and the signaling continues. When aggregates have been cleared — the room has been cleaned up before bedtime — then the SIFI is not diverted away anymore, and it can turn off the stress response,” he said. “Aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it. And so that’s why silencing never happens when you have aggregates, and that’s why cells die.”
A future treatment, Rapé said, would likely involve administration of a drug to turn off the stress response and a drug to keep SIFI turned on to clean up the aggregate mess.
Ubiquitin
Rapé, who is also the Dr. K. Peter Hirth Chair of Cancer Biology, studies the role of ubiquitin — a ubiquitous protein in the body that targets proteins for degradation — in regulating normal and disease processes in humans. In 2017, he discovered that a protein called UBR4 assembles a specific ubiquitin signal that was required for the elimination of proteins that tend to aggregate inside cells.

Only later did other researchers find that mutations in UBR4 are found in some inherited types of neurodegeneration. This discovery led Rapé to team up with colleagues at Stanford University to find out how UBR4 causes these diseases.
“This was a unique opportunity: We had an enzyme that makes an anti-aggregation signal, and when it’s mutated, it causes aggregation disease,” he said. “You put these two things together and you can say, ‘If you figure out how this UBR4 allows sustained cell survival, that probably tells you how aggregates kill cells.'”
They found that UBR4 is actually part of a much larger protein complex, which Rapé dubbed SIFI, and they found that this SIFI machinery was needed when a cell couldn’t sort proteins into its mitochondria. Such proteins that end up at the wrong location in cells tend to clump and, in turn, cause neurodegeneration.
“Surprisingly, though, we found that the core substrates of the SIFI complex were two proteins, one of which senses when proteins don’t make it into mitochondria. That protein detects that something is wrong, and it then activates a kinase that shuts down most of new protein synthesis as part of a stress response, giving the cell time to correct its problem with bringing proteins to the right location,” he said.
This kinase is also degraded through SIFI. A kinase is an enzyme that adds a phosphate group to another molecule, in this case a protein, to regulate important activities in the cell. By helping degrade these two proteins, the SIFI complex turns off the stress response that is caused by clumpy proteins accumulating at the wrong location.
“That’s the very first time that we’ve seen a stress response turned off in an active manner by an enzyme — SIFI — that happens to be mutated in neurodegeneration,” Rapé said.
While investigating how SIFI can turn off the stress response at the right time — only after the room had been cleaned up — the researchers found that SIFI recognizes a short protein segment that acts as a kind of ZIP code that allows proteins or protein precursors to get into the mitochondria, where they are processed. When they are prevented from getting in, they accumulate in the cytoplasm, but SIFI homes in on that ZIP code to eliminate them. The ZIP code looks just like the light switch.
“When you have aggregates accumulating in the cytoplasm, now the ZIP code is still in the cytoplasm, and there’s a lot of it there,” he said. “And it’s the same signal as you would have in the proteins that you want to turn off. So it basically diverts the SIFI complex from the light switch back to the mess. SIFI tries to clean up the mess first, and it cannot turn off the light. And so when you have an aggregate in the cell, the light is always on. And if the light is always on, if stress signaling is always on, the cell will die. And that’s a problem.”
Rapé suspects that many intracellular protein aggregates characteristic of neurodegenerative diseases have similar consequences and may prevent the cell from switching off the stress response. If so, the fact that a drug can turn off the response and rescue brain cells bodes well for the development of treatments for potentially many neurodegenerative diseases.
Already, another stress response inhibitor, a drug called ISRIB discovered at UCSF in 2013, has been shown to improve memory in mice and reduce age-related cognitive decline.
“That means there is the prospect that by manipulating stress silencing, by turning off the light with chemicals, you might target other neurodegenerative diseases, as well,” he said. “At the very least, it’s another way we could help patients with these diseases. In the best possible way, I think it will change how we treat neurodegenerative diseases. That’s why this is a really important story, why I think it’s very exciting.”
Rapé, already a co-founder of two startups, Nurix Therapeutics Inc., and Lyterian Therapeutics, is now looking to develop therapies to silence the stress response while maintaining the cell’s cleanup of protein aggregates.
Co-authors with Rapé are postdoctoral fellows Diane Haakonsen, Michael Heider and Samuel Witus and graduate student Andrew Ingersoll, all of UC Berkeley, and Kayla Vodehnal, Takeshi Uenaka and Marius Wernig of Stanford. The work was supported primarily by the Stinehart-Reed Foundation and the National Institutes of Health (RF1 AG048131, T32MH020016-25).