Publisher Health

Researchers have developed a new method to identify people who are at greater genetic risk of developing Alzheimer’s disease before any symptoms appear — which could help speed creation of novel treatments. Manish Paranjpe of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, United States, and colleagues present these findings in the open-access journal PLOS Genetics on September 1.
People with Alzheimer’s disease experience gradual loss of memory and other cognitive functions. While some treatments can ease symptoms, it has been challenging to develop treatments to prevent or slow disease progression. Some clinical trials investigating potential treatments may have been unsuccessful because they involved patients whose disease was too advanced to be treated. Better methods to identify people at high risk of developing Alzheimer’s could aid treatment research.
To help meet that need, Paranjpe and colleagues analyzed data on 7.1 million common DNA variants — alterations to the standard DNA sequence — from an earlier study that included tens of thousands of people with or without Alzheimer’s. They used this data to develop a novel method that predicts a person’s risk of Alzheimer’s, depending on which DNA variants the person has. Then, they refined and validated the method with data from more than 300,000 additional people.
The researchers note that their DNA-based method is unlikely to be suitable for doctors to predict a patient’s risk of Alzheimer’s because it may be less accurate for non-European populations, it could impact insurance, and it could cause anxiety without the relief of reliable preventive treatments. However, it could be applied to speed Alzheimer’s research.
To demonstrate the potential of the new method, the researchers applied it to determine the risk of Alzheimer’s for each of 636 blood donors and examined whether blood levels of any of 3,000 proteins were higher or lower than normal for those identified as being high-risk. The analysis surfaced 28 proteins that could be linked to Alzheimer’s risk, including several that have never been studied in Alzheimer’s research. Studying these proteins could uncover new directions for drug development.
Future research could help replicate and confirm these findings and expand on them, such as by considering populations with non-European ancestry.
Senior author Dr. Amit V. Khera adds, “We developed a genetic predictor of Alzheimer’s disease associated with both clinical diagnosis and age-dependent cognitive decline. By studying the circulating proteome of healthy individuals with very high versus low inherited risk, our team nominated new biomarkers of neurocognitive disease.”
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A new study of more than 8 million children in Nordic countries suggests the possibility that children born after use of a fertility procedure known as frozen-thawed embryo transfer may have a higher risk of cancer than children born through other means. Nona Sargisian of the University of Gothenburg, Sweden, and colleagues present these findings on September 1 in the open-access journal PLOS Medicine.
Assisted reproductive technology (ART) allows an embryo to be created from a human egg and sperm in a laboratory. A doctor may immediately transfer the embryo to the uterus, or, in a practice that is increasing worldwide, the embryo might be frozen and later thawed before implantation. Prior research suggests that children born after frozen-thawed transfer may have higher short-term risk of certain medical issues than children born after fresh embryo transfer. However, potential long-term medical risks have been less clear.
To boost understanding, Sargisian and colleagues analyzed medical data from 7,944,248 children in Denmark, Finland, Norway, and Sweden. 171,744 were born after the use of ART, and 7,772,474 were conceived spontaneously without the use of assisted reproductive technology. Among those born after the use of ART, 22,630 were born after frozen-thawed transfer.
Statistical analysis of the data from national health registriesshowed that children born after frozen-thawed embryo transfer were at higher risk of cancer than children born after fresh embryo transfer and those without ART. When analyzed as a single group (i.e., those born after frozen-thawed transfer and fresh embryo transfer), however, the use of any type of ART did not have an increased risk of cancer. The most common types of cancer seen in this study were leukemia and tumors of the central nervous system.
The researchers emphasize that their findings should be interpreted with caution, since although the study was large, the number of children born after frozen-thawed embryo transfer who later developed cancer was low (48 cases), which could limit the statistical strength of the analysis.
Nonetheless, the findings may raise concerns about frozen-thawed embryo transfer. Future research will be needed to confirm a possible link between the procedure and increased risk of cancer, as well as any biological mechanisms that may underlie such risk.
Coauthor Ulla-Britt Wennerholm adds, “A higher risk of cancer in children born after frozen-thawed embryo transfer in assisted reproduction, a large study from the Nordic countries found. The individual risk was low, while at a population level it may have an impact due to the huge increase in frozen cycles after assisted reproduction. No increase in cancer was found among children born after assisted reproduction techniques overall.”
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Robots can be better at detecting mental wellbeing issues in children than parent-reported or self-reported testing, a new study suggests.
A team of roboticists, computer scientists and psychiatrists from the University of Cambridge carried out a study with 28 children between the ages of eight and 13, and had a child-sized humanoid robot administer a series of standard psychological questionnaires to assess the mental wellbeing of each participant.
The children were willing to confide in the robot, in some cases sharing information with the robot that they had not yet shared via the standard assessment method of online or in-person questionnaires. This is the first time that robots have been used to assess mental wellbeing in children.
The researchers say that robots could be a useful addition to traditional methods of mental health assessment, although they are not intended to be a substitute for professional mental health support. The results will be presented today (1 September) at the 31st IEEE International Conference on Robot & Human Interactive Communication (RO-MAN) in Naples, Italy.
During the COVID-19 pandemic, home schooling, financial pressures, and isolation from peers and friends impacted the mental health of many children. Even before the pandemic however, anxiety and depression among children in the UK has been on the rise, but the resources and support to address mental wellbeing are severely limited.
Professor Hatice Gunes, who leads the Affective Intelligence and Robotics Laboratory in Cambridge’s Department of Computer Science and Technology, has been studying how socially-assistive robots (SARs) can be used as mental wellbeing ‘coaches’ for adults, but in recent years has also been studying how they may be beneficial to children.

Mount Sinai researchers have published results that show encouraging therapeutic options for patients with the blood cancer multiple myeloma after first-line treatment with bispecific antibodies fails. Bispecific antibodiesare a type of antibody that can bind to two different antigens at the same time — they are meant to enhance the immune system’s destruction of tumor cells.
While new T cell-based immunotherapies, or “T-cell redirection” therapies, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies have revolutionized cancer treatment, doctors still need to determine what second-line treatments (also known as salvage therapy) are effective after a patient relapses. In the August 26 online edition of Blood Advances, Mount Sinai researchers report that sequential use of different T-cell redirection therapies in these multiple myeloma patients is possible and could lead to good patient outcomes and survival.
In a retrospective analysis, researchers identified 58 multiple myeloma patients who participated in a bispecific antibodies clinical trial at Mount Sinai and underwent salvage therapy due to relapse. Patients were followed for an average of 30.5 months after the end of the trial and underwent an average of two salvage therapies over that period.
Nineteen patients received T-cell redirection therapy as a first salvage therapy, and the rest received a non-T-cell redirection therapy, such as chemotherapy. Thirty-two percent of patients who underwent T-cell redirection therapy as a first salvage therapy needed to undergo a second salvage therapy due to relapse or nonresponse to therapy. In a significant contrast, 79 percent of the patients treated with a non-T-cell redirection therapy needed to undergo a second salvage therapy. Some of this group of patients had T-cell redirection therapy as their second salvage therapy, resulting in a total of 28 patients who received T-cell redirection as either a first salvage therapy or second salvage therapy.
Depth and duration of response to the first bispecific antibodies treatment did not predict response to the second T-cell redirection therapy, indicating that even if patients did not respond to an initial T-cell redirection therapy, there may still be an option to effectively treat with a second course. The overall response rate of the 19 patients who transitioned from the initial bispecific antibodies to T-cell redirection therapy as a first salvage therapy was 84 percent, compared to 49 percent in those who received other types of therapies.
“As the clinical use and advancement of T-cell redirection therapies continue to grow, effective strategies are needed to manage outcomes for patients who relapse or are unresponsive to this initial treatment,” said senior author Samir Parekh, MD, Director of Translational Research in Myeloma, co-leader of the Cancer Clinical Investigation program at The Tisch Cancer Institute, and a member of the Icahn Genomics Institute at the Icahn School of Medicine at Mount Sinai. “This study shows patients relapsing after initial bispecific antibodies therapy can benefit from a second bispecific antibody or CAR-T cell therapy.”
Studies are underway to understand how T cells function after initial T-cell redirection therapy and how they are activated in sequential bispecific antibodies and CAR-T cell treatments. “Future clinical trials incorporating sequential combinations of T-cell redirection therapy will build upon these findings to further develop treatment guidelines and improve long-term outcomes for multiple myeloma patients,” Dr. Parekh said.
This work was supported by the National Cancer Institute (NCI) R01 CA244899 and CA252222.
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New findings from Flinders University have demonstrated a molecular link between COVID-19 and serotonin cells in the gut.
The research could help provide further clues to what could be driving COVID-19 infection and disease severity and supports previous evidence that antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), could reduce the severity of COVID symptoms.
COVID-19 displays an array of symptoms, which can regularly include gastrointestinal issues such as diarrhoea. Recent research has indicated that these gut symptoms in COVID-19 patients worsen with the severity of the disease, and this is linked to heightened gut-derived serotonin, released to cause gut dysfunction, increasing the body’s immune response and potentially worsening patient outcomes.
Published in the world’s leading gastrointestinal research journal Gut, this new collaborative study involved three Flinders research teams, including teams led by ARC DECRA Fellow Dr Alyce Martin and FAME Director of Bioinformatics and Human-Microbe Interactions, Professor Robert Edwards.
“Our study endeavoured to understand whether the gut could be a site of disease transmission and what genes might be associated with the virus entering the cells lining the gut wall,” says study senior author Professor Damien Keating, Deputy Director of the Flinders Health and Medical Research Institute and Head of the Gut Sensory Systems research group.
The researchers looked at gene expression amongst the different cell types that line the gut wall, analysing whole genome sequences from thousands of individual cells from within the intestine.

A new study reveals how a rare genetic mutation leads to intellectual disability. The P212L mutation in an enzyme called CaMKIIalpha, which is important for learning and memory, is known to be linked to intellectual disability. However, the exact process by which the mutation affected the enzyme’s activity was unclear, until now. A newly developed method of protein analysis has shown that the P212L mutation causes dramatically more activation of CaMKIIalpha. This has enabled researchers to identify a potential treatment using existing medicine, and this new method could be adapted to analyze other genetic causes of disability and disease in the future.
About 1% of the global population lives with an intellectual disability. There are several commonly known causes including infection, injury or genetic conditions. CaMKIIalpha is an enzyme that mediates biochemical reactions in the brain and is important for our ability to learn. Typical learning requires that CaMKIIalpha activity is regulated at appropriate levels and at the appropriate timing, and irregularities with it have previously been linked to a variety of neurological disorders. One known cause of intellectual disability is a P212L mutation in CaMKIIalpha. Although the association between intellectual disability and the mutation is known, exactly how the enzyme’s mutation alters its function was not previously understood.
The mutation of P212L is very rare, but a patient was identified in Japan who then took part in a study with researchers from the University of Tokyo and Nagoya University. “This is only the fourth known case of this P212L mutation in the world. However, the relationship between this single gene mutation and symptoms is relatively clear, making it important in the study of intellectual disability,” said Hajime Fujii, lecturer from the Graduate School of Medicine at the University of Tokyo.
Since reactions at this scale are not directly visible to our eyes, they must be monitored through other techniques. However, these experiments are usually laborious and time consuming. “It is difficult to process many samples in parallel and not possible to measure enzyme activity in physiological conditions, such as living cells or synapses. We wanted something more simple, scalable, sensitive and quantitative. So, we developed a method to measure enzyme activity by fluorescent probe,” explained Fujii. “This can tell us the progress of a biochemical reaction by its brightness or color. In order to create a fluorescent probe, we had to couple the biochemical reaction, such as molecular binding or changes in protein shape (that occur at the scale of a nanometer), with fluorescence brightness or color. So, we used a physical phenomenon called FRET (Förster resonance energy transfer), with which the probe can change relative brightness between two colors according to changes of the CaMKIIalpha that occur when it is activated. We call our approach a FRET-based kinase phenotyping strategy.”
This new method enabled the team to rapidly and accurately analyze nearly a hundred cell extracts and study their biological activity. What it found was that CaMKIIalpha with the P212L mutation exhibited enhanced activation compared to usual. This means that rewiring or changes in the brain that usually occur during learning may possibly be irregular in people with this mutation, compared to people without it. The researchers also found that in neurons, taken from rats in this study, the CaMKIIalpha response to stimulation was increased. The activation response of the enzyme rose faster and fell slower, again demonstrating an unusually enhanced response.
The team hopes that its research will help to identify treatment options for genetically based intellectual disabilities. In this case, it found that memantine, a drug currently used to treat symptoms of Alzheimer’s disease, caused a suppression of the P212L mutation’s effect in neurons. “The next step would be to determine in more detail how irregular CaMKIIalpha activation causes intellectual disability and examine whether suppressing irregular activation with memantine can treat intellectual disability,” said Fujii.
“So far, there has been no effective medical treatment for children with genetically based intellectual disability. This study can offer the possibility of treatment to patients with intellectual disability who have this rare variant of CaMKII” said Assistant Professor Hiroyuki Kidokoro from Nagoya University, a paper co-author and pediatrician who worked with the patient.
Looking to the future, Fujii said, “Mutations in CaMKIIalpha have been related to other neurodevelopmental disorders, so we may be able to clarify the development of and treatment strategies for these mutations in the same way, by applying this FRET-based kinase phenotyping platform. To apply our strategy to mutations of other genes that cause various diseases, we will need fluorescent probes to measure the functions of the genes. Currently, fluorescent probes are available for some genes, but not others, so it will be necessary to develop new fluorescent probes, which may take some time.”
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Overweight increases the risk of an imbalance in sugar metabolism and even of diabetes. A research group at the University of Basel has now shown the opposite is true as well: deficits in the body’s insulin production contribute to overweight.
Poor nutrition, too little movement and too many pounds on the scale — lifestyle influences the risk of metabolic diseases like diabetes. But the relationship works the other way round as well, as a research group led by Dr. Daniel Zeman-Meier of the university’s Department of Biomedicine and the University Hospital of Basel reports. If insulin production is compromised, as is the case in the early stages of type 2 diabetes, this can contribute to overweight. The researchers report their findings in the journal Nature Communications.
When hormone activation goes awry
The research team focused on protease PC1/3, a key enzyme in the body that transforms various inactive hormone precursors into the final, active forms. If this enzyme isn’t functioning properly in a person, the result can be severe endocrine disorders. The consequences include a feeling of uncontrollable hunger and severe overweight.
“Until now, it was assumed that this dysregulation is caused by a lack of activation of satiety hormones,” explains the study’s leader, Dr. Zeman-Meier. “But when we turned off PC1/3 in the brains of mice, the animals’ body weight did not change significantly.” The researchers concluded from this that something other than a brain malfunction must be responsible.
Incorrect activation of insulin leads to hunger and overweight
In their next step, they tested whether overweight could be caused by incorrect activation of other hormones. PC1/3 activates insulin, among other things. Insulin plays a key role in the regulation of blood sugar and fat metabolism. “Investigating the role of insulin production as a cause of overweight was obvious,” says Dr. Zeman-Meier. The researchers shut off PC1/3 specifically in the insulin-producing beta cells of the pancreas in mice. The animals consumed significantly more calories and soon became overweight and diabetic.
An important mechanism in humans
“These results are also interesting because PC1/3 is reduced in the pancreas of patients with prediabetes,” says Professor Marc Donath, the research group leader and final author of the study. This indicates that incorrect insulin activation could be not only a consequence, but also a cause of overweight.
But PC1/3 is also important in the weight regulation of healthy individuals, Donath emphasizes. The researchers were able to show that the gene expression of PC1/3 in the pancreas is negatively correlated with body weight in the general population — meaning that sufficient PC1/3 promotes a healthy body weight.
The finding that a defect in the insulin-producing beta cells is a trigger of overweight opens up new therapeutic possibilities. For example, it is conceivable that medications could be used to reduce the production of immature insulin precursors, creating a new tool in the fight against overweight and diabetes.
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A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma, a highly lethal type of brain cancer. The researchers achieved the outcome using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other supplies the energy required for rapid tumor growth. The work found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.
The study was led by Ph.D. student Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH) in the USA. The paper was published in the scientific journal Brain and was highlighted with special commentary.
The researchers explain: “Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors.”
Dr. Mayo: “Here, we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells. Specifically, we studied astrocytes — a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth.”
Using an animal model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4-5 weeks. Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated animals survived. Moreover, even after discontinuing treatment, most animals survived.
Dr. Mayo: “In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse — indicating that the astrocytes are essential to tumor progression and survival. Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?” To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors.
They found two main differences — thereby identifying the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma. Dr. Mayo: “The tumor mass includes up to 40% immune cells — mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes ‘persuade’ them to ‘change sides’ and support the tumor instead of attacking it. Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly — thereby protecting the tumor and facilitating its growth.”
The second change through which astrocytes support glioblastoma is by modulating their access to energy — via the production and transfer of cholesterol to the tumor cells. Dr. Mayo: “The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself — namely in the astrocytes’ ‘cholesterol factory’, which usually supplies energy to neurons and other brain cells. We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells. Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor.”
Next, the researchers engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially ‘starved’ to death in just a few days. These remarkable results were obtained in both animal models and glioblastoma samples taken from human patients and are consistent with the researchers’ starvation hypothesis.
Dr. Mayo notes: “This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability — the tumor’s dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity.”
The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above. The researchers explain: “For each patient, we examined the expression levels of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients.”
Dr. Mayo concludes: “Currently, tools to eliminate the astrocytes surrounding the tumor are available in animal models, but not in humans. The challenge now is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors.”

As public health officials around the world contend with the latest surge of the COVID-19 pandemic, researchers at Drexel University have created a computer model that could help them be better prepared for the next one. Using machine learning algorithms, trained to identify correlations between changes in the genetic sequence of the COVID-19 virus and upticks in transmission, hospitalizations and deaths, the model can provide an early warning about the severity of new variants.
More than two years into the pandemic, scientists and public health officials are doing their best to predict how mutations of the SARS-CoV-2 virus are likely to make it more transmissible, evasive to the immune system and likely to cause severe infections. But collecting and analyzing the genetic data to identify new variants — and linking it to the specific patients who have been sickened by it — is still an arduous process.
Because of this, most public health projections about new “variants of concern” — as the World Health Organization categorizes them — are based on surveillance testing and observation of the regions where they are already spreading.
“The speed with which new variants, like Omicron have made their way around the globe means that by the time public health officials have a good handle on how vulnerable their population might be, the virus has already arrived,” said Bahrad A. Sokhansanj, PhD, an assistant research professor in Drexel’s College of Engineering who led development of the computer model. “We’re trying to give them an early warning system — like advanced weather modeling for meteorologists — so they can quickly predict how dangerous a new variant is likely to be — and prepare accordingly.”
The Drexel model, which was recently published in the journal Computers in Biology and Medicine, is driven by a targeted analysis of the genetic sequence of the virus’s spike protein — the part of the virus that allows it to evade the immune system and infect healthy cells, it is also the part known to have mutated most frequently throughout the pandemic — combined with a mixed effects machine learning analysis of factors such as age, sex and geographic location of COVID patients.
Learning to Find Patterns
The research team used a newly developed machine learning algorithm, called GPBoost, based on methods commonly used by large companies to analyze sales data. Via a textual analysis, the program can quickly home in on the areas of the genetic sequence that are most likely to be linked to changes in the severity of the variant.

Evolution is often portrayed as a “tinkering” process, one that makes use of slight modifications to pre-existing capabilities. So how do organisms evolve brand new structures?
A new study by Dr. Zsuzsanna Izsvák from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) and Professor Laurence Hurst from the Milner Centre for Evolution at University of Bath (UK) found evidence that evolution of a new gene underpins the evolution of a new structure found in nerve cells. They describe this unusual gene called piggyBac Transposable Element-derived 1, or PGBD1, in the journal Molecular Biology and Evolution.
“Jumping genes” cause mutations
PGBD1 is one of five related PGBD genes that shows a distinct resemblance to the piggyBac element first identified in insects — hence the name piggyBac Transposable Element-derived. The PiggyBac elements are “jumping genes,” also called transposons. They are able to copy themselves and to move from one location in the genome to another, sometimes introducing mutations or changing functions. PiggyBac transposons arrived into our species by horizontal transfer — similar to how some viruses can integrate their genome into our DNA. However, while the piggyBac transposons have lost their ability to jump around in our DNA over time, five piggyBac Transposable Element-derived genes (PGBD1-5) have been fixed in humans. “We aimed at finding out what potentially useful function the PGBD genes might have,” says Zsuzsanna Izsvák. “For this study, we focused on PGBD1.”
Amongst the five PGBD genes PGBD1 is unique in that it has also incorporated parts of other genes, resulting in a protein that has extra parts that are able to bind other proteins and to bind DNA. PGBD1 is thus a novel gene that is part human gene fragment, part inactive jumping gene.
PGBD1 regulates nerve cells and their “protein traps”
PGBD1 is found only in mammals. It is particularly active in cells that become neurons. The researchers first investigated, where PGBD1 protein binds to DNA, observing that it glues itself in and around genes associated with nerve development. They found PGBD1 controls nerve cell development by blocking genes expressed in mature nerve cells while keeping those genes associated with being pre-nerve cells activated. Reducing the level of PGBD1 in pre-nerve cells caused them to start developing as nerve cells.
One of the genes that PGBD1 protein binds especially attracted their interest. NEAT1 is a strange gene that codes for an RNA which, unusually, doesn’t then go on to make a protein. Instead, this product, a non-coding RNA, makes the backbone of a physical structure, the paraspeckles. These are tiny structures in the nuclei of some of our cells that act like traps for some RNAs and proteins. The researchers found that in pre-nerve cells PGBD1 protein binds to the NEAT1 gene and stops it from working. However, when PGBD1 levels go down, NEAT1 RNA levels go up, paraspeckles form and cells become mature nerve cells. PGBD1 thus has evolved to be a key regulator of presence or absence of paraspeckles, and thus the regulator of nerve cell development.
Evolution is not random tinkering
What, however, is most intriguing is that paraspeckles are, like PGBD1, also mammal-specific. PGBD1 is then a rare example of a new gene that has evolved to regulate a new structure, albeit a rather small one. Zsuzsanna Izsvák, co-senior author from Max Delbrück Center, says: “This is a really unusual and serendipitous discovery. We have known that duplication of pre-existing genes can underpin the evolution of novelty, but this is a rare example of evolution doing more than just tinkering. This is a novel gene to control a novel structure.” The exciting question now is whether it also plays a role in adult neurons.
Co-senior author Professor Laurence Hurst of the Milner Centre for Evolution at the University of Bath adds: “We have worked out how paraspeckles are controlled, now we just need to work out how the paraspeckle itself evolved. This might be a much harder task as non-coding RNAs like NEAT1 tend to be fast evolving and therefore hard to trace over evolutionary time.”
This coupling between NEAT1 and PGBD1 may also be involved in schizophrenia. While NEAT1 has been previously associated with this neurological disease, the team identified some mutations in PGBD1 that they could show were also common in patients with schizophrenia — one of these mutations changes the protein of PGBD1 while others may control its level. First author Dr Tamas Raskó, at the time of the study a postdoctoral researcher in the group of Zsuzsanna Izsvák: “It is surely more than coincidence that both genes are involved in schizophrenia. It is very unusual to find a mutation that changes a protein that is coupled to this disease. The effects of this mutation must be a priority for further studies.”