NS/ New bioluminescence imaging technique illuminates oxygen’s journey in the brain
Neuroscience biweekly vol. 107, 27th March — 10th April
TL;DR
- A new bioluminescence imaging technique, described in the journal Science, has created highly detailed, and visually striking, images of the movement of oxygen in the brains of mice. The method, which can be easily replicated by other labs, will enable researchers to more precisely study forms of hypoxia in the brain, such as the denial of oxygen to the brain that occurs during a stroke or heart attack. The new research tool is already providing insight into why a sedentary lifestyle may increase the risk for diseases like Alzheimer’s.
- Inflammation in the brain is rarely seen as a good thing; research has linked it to diseases including Alzheimer’s, Parkinson’s and neuropsychiatric symptoms such as anxiety. But a new study from Albert Einstein College of Medicine scientists puts a different spin on inflammation’s role in the brain, one that could have implications for drugs that target inflammatory pathways. The research, published in Nature, suggests that DNA damage and inflammation in hippocampal neurons are critical for long-term memory formation, at least in mice.
- A new study is among the first of its kind to separate activity relating to emotion generation from emotion regulation in the human brain. The findings provide new insights that could help inform therapeutic treatments regarding mental health and drug addiction.
- Trinity scientists have developed a novel test — using an existing diagnostic procedure as its basis — that has the potential to be applied in clinical trials that target the Epstein-Barr Virus.
- Changes in personality, behavior, and language are hallmarks of frontotemporal dementia (FTD), the most common form of dementia in patients under the age of 65, which is associated with degeneration of the frontal and temporal lobes of the brain. Researchers observed that in most people with FTD whom they studied, these structures pile up, but in those with the protective form, they are virtually absent. The research could pave the way for better treatments in the future.
- Most human nerve cells last a lifetime without renewal. A trait echoed within the cells’ components, some enduring as long as the organism itself. New research discovered RNA, a typical transient molecule, in the nerve cells of mice that remain stable for their entire lives. Published in Science, these findings contribute to unraveling the complexities of brain aging and associated diseases.
- A multidisciplinary team of scientists led by the University of Helsinki reports that a progressive neurodegenerative disease can be triggered by a viral infection. The mechanism relates to mitochondrial roles in antiviral defense mechanisms.
- A research group centered at the University of California San Diego School of Medicine has drilled deep into a dataset of over 3 million individuals compiled by the direct-to-consumer genetics company 23andMe, Inc., and found intriguing connections between genetic factors influencing alcohol consumption and their relationship with other disorders.
- Cutting out the carbs could lessen the symptoms of bipolar disorder and schizophrenia, according to a new study. In a small pilot trial of 21 adults (16 with bipolar disorder, 5 with schizophrenia), researchers found that a 4-month-long low-carbohydrate, high-fat diet improved the majority of participants’ mental health scores.
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The latest news and research
Oxygen imaging of hypoxic pockets in the mouse cerebral cortex
by Beinlich FRM, Asiminas A, Untiet V, et al in Science
A new bioluminescence imaging technique, described in the journal Science, has created highly detailed, and visually striking, images of the movement of oxygen in the brains of mice. The method, which can be easily replicated by other labs, will enable researchers to more precisely study forms of hypoxia in the brain, such as the denial of oxygen to the brain that occurs during a stroke or heart attack. The new research tool is already providing insight into why a sedentary lifestyle may increase risk for diseases like Alzheimer’s.
The human brain consumes vast amounts of energy, which is almost exclusively generated from a form of metabolism that requires oxygen. While the efficient and timely delivery of oxygen is known to be critical to healthy brain function, the precise mechanics of this process have largely remained hidden from scientists.
“This research demonstrates that we can monitor changes in oxygen concentration continuously and in a wide area of the brain,” said Maiken Nedergaard, co-director of the Center for Translational Neuromedicine (CTN), which is based at both the University of Rochester and the University of Copenhagen. “This provides us a with a more detailed picture of what is occurring in the brain in real time, allowing us to identify previously undetected areas of temporary hypoxia, which reflect changes in blood flow that can trigger neurological deficits.”
The new method employs luminescent proteins, chemical cousins of the bioluminescent proteins found in fireflies. These proteins, which have been used in cancer research, employs a virus that delivers instructions to cells to produce a luminescent protein in the form of an enzyme. When the enzyme encounters a second chemical compound, a substrate called furimazine, the chemical reaction generates light.
Like many important scientific discoveries, employing this process to image oxygen in the brain was stumbled upon by accident. Felix Beinlich, PhD, an assistant professor in the CTN at the University of Copenhagen, had originally intended to use the luminescent protein to measure calcium activity in the brain. It became apparent that there was an error in the production of the proteins, causing a months-long delay in the research.
While Beinlich waited for a new batch from the manufacturer, he decided move forward with the experiments to test and optimize the monitoring systems. The virus was used to deliver enzyme-producing instructions to astrocytes, ubiquitous support cells in the brain that maintain the health and signaling functions of neurons, and the substrate was injected into the brain via a craniotomy. The recordings revealed activity, identified by a fluctuating intensity of bioluminescence, something that the researchers suspected, and would later confirm, reflected the presence and concentration of oxygen.
“The chemical reaction in this instance was oxygen dependent, so when there is the enzyme, the substrate, and oxygen, the system starts to glow,” said Beinlich.
While existing oxygen monitoring techniques provide information about a very small area of the brain, the researchers were able to observe, in real time, a large section of the cortex of the mice. The intensity of the bioluminescence corresponded with the concentration of oxygen, which the researchers demonstrated by changing the amount of oxygen in the air the animals were breathing. Changes in light intensity also corresponded with sensory processing. For example, when the mice’s whiskers were stimulated with a puff of air, the researchers could see the corresponding region of the brain light up.
The brain cannot survive long without oxygen, a concept demonstrated by the neurological damage that quickly follows a stroke or heart attack. But what happens when very small parts of the brain are denied oxygen for brief periods? This question was not even being asked by researchers until the team in the Nedergaard lab began to look closely at the new recordings. While monitoring the mice, the researchers observed that specific tiny areas of the brain would go dark, sometimes for minutes, meaning that the oxygen supply was being cut off.
Oxygen is circulated throughout the brain via a vast network of arteries and smaller capillaries–or microvessels–which permeate brain tissue. Through a series of experiments, the researchers were able to determine that oxygen was being denied due to capillary stalling, which occurs when white blood cells temporarily block microvessels and prevent the passage of oxygen carrying red blood cells. These areas, which the researchers named “hypoxic pockets,” were more prevalent in the brains of mice during a resting state, compared to when the animals were active. Capillary stalling is believed to increase with age and has been observed in models of Alzheimer’s disease.
“The door is now open to study a range of diseases associated with hypoxia in the brain, including Alzheimer’s, vascular dementia, and long COVID, and how a sedentary lifestyle, aging, hypertension, and other factors contribute to these diseases,” said Nedergaard. “It also provides a tool to test different drugs and types of exercise that improve vascular health and slow down the road to dementia.”
Formation of memory assemblies through the DNA-sensing TLR9 pathway
by Jovasevic V, Wood EM, Cicvaric A, et al in Nature
Inflammation in the brain is rarely seen as a good thing; research has linked it to diseases including Alzheimer’s, Parkinson’s and neuropsychiatric symptoms such as anxiety. But a new study from Albert Einstein College of Medicine scientists puts a different spin on inflammation’s role in the brain, one that could have implications for drugs that target inflammatory pathways. The research, published in Nature, suggests that DNA damage and inflammation in hippocampal neurons are critical for long-term memory formation, at least in mice.
The hippocampus is well-known for its role in memory formation, organization and storage. It’s in this part of the brain that our individual experiences are represented as neural assemblies in hippocampal and cortical circuits. How these assemblies form — and are maintained — has been the focus of much research and debate in neuroscience.
The most widely accepted mechanism is stimulus-induced long-term potentiation of synaptic activity; put simply, this means that neuronal connections become stronger after repeated stimulation over a long period of time, which underlies memory formation and retainment. Other mechanisms of action have also been proposed that suggest memory is influenced by built-in cellular programs that are present within individual neurons from the early stages of development.
The research team behind the Nature study wanted to explore whether an overarching process — one that integrates stimulus-dependent and pre-existing mechanisms — could be involved in memory formation and maintenance. The research was led by Dr. Jelena Radulovic, MD, professor in the Dominick P. Purpura Department of Neuroscience, professor of psychiatry and behavioral sciences and the Sylvia and Robert S. Olnick Chair in Neuroscience at Einstein.
Radulovic and colleagues subjected male and female mice to contextual fear conditioning (CFC), where mice were placed in a novel environment for three minutes before receiving a brief, mild electric shock to the foot. This assay is designed to induce episodic memory; when the animal is returned to the environment, it typically demonstrates a freezing response if it remembers the environment and associates it with the electric shock.
Using techniques including bulk RNA-sequencing (RNA-seq) and immunofluorescent labeling, Radulovic and colleagues analyzed gene expression and DNA breaks in hippocampal neurons. The neurons had been extracted from the mice either 96 hours or 21 days after CFC.
“We previously reported that the 21-day gene expression repertoire revolved around cilium and extracellular matrix genes needed for PNN formation, but the 96-hour gene expression profiles associated with the shaping of recent memory representations remained unexplored,” the authors said.
After CFC, genes involved in inflammatory signaling were, to the researcher’s surprise, upregulated. “We observed strong activation of genes involved in the Toll-like receptor 9 (TLR9) pathway,” said Radulovic, who is also director of the Psychiatry Research Institute at Montefiore Einstein (PRIME).
The TLR9 pathway is typically triggered by the presence of small fragments of pathogenic DNA.
“At first we assumed the TLR9 pathway was activated because the mice had an infection,” said Radulovic. “But looking more closely, we found, to our surprise, that TLR9 was activated only in clusters of hippocampal cells that showed DNA damage.”
DNA damage can be triggered by brain activity, but it’s often repaired within just a few minutes. In the hippocampal neurons analyzed in the study, double strand (ds) DNA breaks persisted, and were substantial. When dsDNA breaks were at a maximal level, the researchers observed nuclear envelope ruptures, which allowed for other molecules produced by DNA damage to be released into the cytoplasm, activating the TLR9 pathway.
This pathway triggered the formation of DNA repair complexes at an unexpected location — the centrosomes. Centrosomes are membrane-free organelles that, in dividing cells, help to coordinate the process of cell division. Neurons, however, do not divide. Instead, it appears that the DNA complexes forming at the centrosomes in neurons are helping to organize individual neurons into memory assemblies.
“Cell division and the immune response have been highly conserved in animal life over millions of years, enabling life to continue while providing protection from foreign pathogens,” Radulovic explained. “It seems likely that over the course of evolution, hippocampal neurons have adopted this immune-based memory mechanism by combining the immune response’s DNA-sensing TLR9 pathway with a DNA repair centrosome function to form memories without progressing to cell division.”
An important finding of the study — in Radulovic’s opinion — is that, during the week whereby this inflammatory process was ongoing, hippocampal neurons became resistant to new or similar environmental stimuli:
“This is noteworthy because we’re constantly flooded by information, and the neurons that encode memories need to preserve the information they’ve already acquired and not be ‘distracted’ by new inputs,” she said.
“The recruitment of individual neurons to assemblies is essential not only for encoding individual memories, but also for protecting them from streams of incoming information over time, ensuring stability and persistence of memory representations. On the basis of the evidence presented here, we suggest that in distinct populations of hippocampal CA1 excitatory neurons, this is achieved through learning-induced TLR9 signalling linking DNA damage to DDR,” the authors said in the paper.
In knock-out experiments, blocking the TLR9 inflammatory pathway in hippocampal neurons impaired long-term memory formation, and triggered a high frequency of DNA damage.
This data could have implications for drugs that inhibit TLR9, Radulovic said:
“Genomic instability is considered a hallmark of accelerated aging as well as cancer and psychiatric and neurodegenerative disorders such as Alzheimer’s. Drugs that inhibit the TLR9 pathway have been proposed for relieving the symptoms of long COVID. But caution needs to be shown because fully inhibiting the TLR9 pathway may pose significant health risks.”
A systems identification approach using Bayes factors to deconstruct the brain bases of emotion regulation
by Ke Bo, Thomas E. Kraynak, Mijin Kwon, Michael Sun, Peter J. Gianaros, Tor D. Wager in Nature Neuroscience
Ever want to scream during a particularly bad day, but then manage not to? Thank the human brain and how it regulates emotions, which can be critical for navigating everyday life. As we perceive events unfolding around us, the ability to be flexible and reframe a situation impacts not only how we feel, but also our behavior and decision-making.
In fact, some of the problems associated with mental health relate to individuals’ inability to be flexible, such as when persistent negative thoughts make it hard to perceive a situation differently.
To help address such issues, a new Dartmouth-led study is among the first of its kind to separate activity relating to emotion generation from emotion regulation in the human brain.
“As a former biomedical engineer, it was exciting to identify some brain regions that are purely unique to regulating emotions,” says lead author Ke Bo, a postdoctoral researcher in the Cognitive and Affective Neuroscience Lab (CANlab) at Dartmouth. “Our results provide new insight into how emotion regulation works by identifying targets which could have clinical applications.”
For example, the systems the researchers identified could be good targets for brain stimulation to enhance the regulation of emotion.
Using computational methods, the researchers examined two independent datasets of fMRI studies obtained earlier by co-author Peter Gianaros at the University of Pittsburgh. Participants’ brain activity was recorded in an fMRI scanner as they viewed images that were likely to draw a negative reaction such as a bloody scene or scary- looking animals.
The participants were then asked to recontextualize the stimulus by generating new kinds of thoughts about an image to make it less aversive, before a neutral image was presented followed by another dislikable image. By examining the neural activity, researchers could identify the brain areas that are more active when emotions are regulated versus when emotions are generated.
The new study reveals that emotion regulation, also known in neuroscience as “reappraisal,” involves particular areas of the anterior prefrontal cortex and other higher-level cortical hierarchies whose role in emotion regulation had not previously been isolated with this level of precision. These regions are involved in other high-level cognitive functions and are important for abstract thought and long-term representations of the future.
The more people are able to activate these emotion regulation-selective brain regions, the more resilient they are to experiencing something negative without letting it affect them personally. These findings build on other research linking these areas to better mental health and the ability to resist temptations and avoid drug addiction.
The results also demonstrated that the amygdala, which is known as the threat-related brain region responsible for negative emotion and has long been considered an ancient subcortical threat center, responds to aversive experiences the same way, whether people are using their thoughts to self-regulate down-regulate negative emotion or not.
“It’s really the cortex that is responsible for generating people’s emotional responses, by changing the way we see and attach meaning to events in our environments,” says Bo.
The researchers were also interested in identifying the neurochemicals that interact with emotion regulation systems. Neurotransmitters like dopamine and serotonin shape how networks of neurons communicate and are targets for both illicit drugs and therapeutic treatments alike. Some neurotransmitters may be important for enabling the ability to self-regulate or “down-regulate.”
The team compared the emotion regulation brain maps from the two datasets to neurotransmitter binding maps from 36 other studies. The systems involved in regulating negative emotion overlapped with particular neurotransmitter systems.
“Our results showed that receptors for cannabinoids, opioids, and serotonin, including 5H2A, were especially rich in areas that are involved in emotion regulation,” says senior author Tor Wager, the Diana L. Taylor Distinguished Professor in Neuroscience and director of the Dartmouth Brain Imaging Center at Dartmouth. “When drugs that bind to these receptors are taken, they are preferentially affecting the emotion regulation system, which raises questions about their potential for long-term effects on our capacity to self-regulate.”
Serotonin is well-known for its role in depression, as the most widely used antidepressant drugs inhibit its reuptake in synapses, which transmit signals from one neuron to another.
5H2A is the serotonin receptor most strongly affected by another exciting new type of treatment for mental health — psychedelic drugs. The study’s findings suggest that the effects of drugs on depression and other mental health disorders may work in part by altering how we think about life events and our ability to self-regulate. This may help explain why drugs, particularly psychedelics, are likely to be ineffective without the right kind of psychological support. The study could help improve therapeutic approaches by increasing our understanding of why and how psychological and pharmaceutical approaches need to be combined into integrated treatments.
“It’s important to consider these types of connections that come from basic science,” says Wager. “Understanding drug effects requires understanding the brain systems involved and what they’re doing at a cognitive level.”
Disease-modifying treatments for multiple sclerosis affect measures of cellular immune responses to EBNA-1 peptides
by Dungan L, Dunne J, Savio M, et al. in Neurol Neuroimmunol Neuroinflamm
Trinity scientists have developed a novel test — using an existing diagnostic procedure as its basis — that has the potential to be applied in clinical trials that target the Epstein Barr Virus.
A team of research scientists at Trinity College have developed a new and unique blood test to measure the immune response to the Epstein Barr Virus (EBV) which is the leading risk factor for developing multiple sclerosis (MS). Their findings are published in the journal Neurology Neuroimmunology and Neuroinflammation and have implications for future basic research in further understanding the biology of EBV in MS, but also has the potential to be applied in clinical trials that target the virus.
MS is a chronic neurological disease with no known cure. It affects approximately three million people worldwide and is the second leading cause of disability in young adults. There is a pressing need for better treatments.
A range of viruses relating to MS have been studied in the past but none have had such compelling evidence as EBV. The question the team considered was why do some people who have known MS have a rogue immune response to EBV, a common viral infection that is generally asymptomatic?
To answer this, scientists measured the cellular response of MS patients to EBNA-1, a part of the EBV that can mimic the myelin coating of nerves which are the principal site of attack of the immune system in MS. The team found that the immune response is higher to EBNA-1 in people with MS compared to those with epilepsy, or the healthy control group. The team also showed that this cellular response is impacted by currently approved medications for MS which target the immune system, but not the virus. The immune response to EBNA-1 was found to be lower in people who are taking B cell depleting medications compared to people with MS not taking medication and the level recorded was equivalent to healthy controls.
B cell depleting medications are effective for reducing MS disease activity. It is not known however, how exactly they work. Many people believe that reducing B cells reduces EBV levels, as EBV can lie dormant within B cells. The scientists do not prove this theory, but do show that the immune response to EBV in MS is equal to healthy controls when these medications are used. The team believe that this supports the need for more selective reduction in EBV rather than targeting all B cells. This is of importance as B cells play an important role in fighting infection and an unselective approach can lead to unwanted side effects.
The Trinity researchers are the first team of scientists to capture the immune response to EBNA-1 using whole blood samples carried out exclusively with equipment that is used in the hospital laboratory day to day. This builds on previous research that used extensive pre-processing in research laboratories. We believe this is of importance as it shows the ability for the test to be run elsewhere and at scale without a need for new equipment or personnel.
This research is important because a standard blood test that was processed in a hospital laboratory provides important information on the immune system’s response to EBNA-1. This response appears to be at the heart of the pathogenesis of MS. The ability to measure this in a scalable test, that was developed using an existing diagnostic test as its basis, has implications for future basic research in further understanding the biology of EBV in MS. But the test also has the potential to be applied in clinical trials that target the virus. This would mean that there is the potential to directly measure the immune response to any potential antiviral treatments, rather than measuring MS outcome measures alone.
Speaking on the potential benefits of this research, Dr Hugh Kearney, Neurologist, School of Medicine, Trinity College and lead author said:
“In the short term the benefit of this research is likely to be for the research community in MS. We believe the approach adopted in this test that uses whole blood samples on a robust hospital-based platform will facilitate adoption in other centres and also replication of the results with a view towards validation. In the medium term, if validated, then this would be of benefit to researchers involved in clinical trials in MS. Long term benefits will be for people with MS, who live with a chronic neurological illness as new treatments tested in clinical trials have the potential to reduce the burden of this potentially disabling disease.The next step for our team is to develop a longitudinal study. We aim to do this by recruiting newly diagnosed people with MS and measuring this blood test before treatment has started and then repeating the blood test at an interval to show that B cell depletion directly impacts on the cellular response to EBNA-1 in MS.”
TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia
by Marks JD, Ayuso VE, Carlomagno Y, et al. in Sci Transl Med
Changes in personality, behavior and language are hallmarks of frontotemporal dementia (FTD), the most common form of dementia in patients under the age of 65, which is associated with degeneration of the frontal and temporal lobes of the brain. Researchers have known that a less common protective variant of a gene called TMEM106B may slow disease progression, and now they have new insight into how parts of the protein produced by the TMEM106B gene may increase risk and cause the disease to accelerate. They think the key may lie in the formation of fibrils, or tiny fiber-like structures produced by part of this protein, that sometimes get tangled up in the brain through an unknown process. Researchers observed that in most people with FTD whom they studied, these structures pile up, but in those with the protective form, they are virtually absent. The research could pave the way for better treatments in the future.
Only recently has the research community discovered that the TMEM106B protein forms these thread-like structures in the brain.
Mayo Clinic researchers in Florida and colleagues set out to determine the link between these TMEM106B structures, the protective TMEM106B genetic variant and FTD. First, they compared disease duration in deceased FTD patients who had donated their brain tissue to the Mayo Clinic Brain Bank. They found that those with the protective variant lived an average of three years longer. This suggests that the disease progressed slower in those patients.
Then, they created an antibody that would allow them to detect the amount of fiber-like structures in the human brain tissue.
Across all FTD cases that researchers analyzed from the brain bank — more than 250 samples — they found that most patients had a relatively high level of these thread-like structures in their brains. However, those with only the protective variant of TMEM106B had little to none. There was a positive correlation between the amount of TMEM106B structures and the level of another pathologic protein called TDP-43, which is strongly associated with FTD.
“It was striking to see that there was no buildup of fibrils in those with the protective variant. We think that likely has something to do with how TMEM106B protects against FTD or alters the disease course, but more work needs to be done to investigate that,” says Jordan Marks, an M.D.–Ph.D. student with the Mayo Clinic Graduate School of Biomedical Sciences and first author of the paper. “We also think that these fibrils could one day serve as biomarkers to help clinicians determine FTD prognosis or severity.”
The researchers say the findings have implications for future clinical studies.
“Our research provides evidence that genetic variants in TMEM106B are an essential factor to consider in study groups of patients with FTD,” says Casey Cook, Ph.D., a Mayo Clinic neuroscientist and co-corresponding author of the paper. “The work also suggests novel therapeutic interventions to prevent the buildup of the tangled fiber-like structures might one day reduce disease risk or slow disease progression.”
The next steps in the team’s research include validating these results in additional patient study groups and examining the network of interacting proteins associated with FTD to provide further insight into how the TMEM106B protein buildup contributes to disease.
In a related study, also published in Science Translational Medicine, Mayo Clinic researchers and collaborators discovered novel peptides in brain and cerebrospinal fluid produced when TDP-43, also implicated in amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, becomes dysfunctional. Their findings could provide the framework for the development of clinical-grade tests to measure TDP-43 pathology in living patients.
Lifelong persistence of nuclear RNAs in the mouse brain
by Sara Zocher, Asako McCloskey, Anne Karasinsky, Roberta Schulte, Ulrike Friedrich, Mathias Lesche, Nicole Rund, Fred H. Gage, Martin W. Hetzer, Tomohisa Toda in Science
Most human nerve cells last a lifetime without renewal. A trait echoed within the cells’ components, some enduring as long as the organism itself. New research by Martin Hetzer, molecular biologist and president of the Institute of Science and Technology Austria (ISTA), and colleagues discovered RNA, a typical transient molecule, in the nerve cells of mice that remain stable for their entire lives. Published in Science, these findings contribute to unraveling the complexities of brain aging and associated diseases.
After two decades in the United States, Martin Hetzer returned home to Austria in 2023 to become the 2nd President of the Institute of Science and Technology Austria (ISTA). A year into his new role, the molecular biologist remains engaged in the realm of aging research.
Hetzer is fascinated by the biological puzzles surrounding the aging processes in organs like the brain, heart, and pancreas. Most cells comprising these organs are not renewed throughout a human’s entire life span. Nerve cells (neurons) in the human brain, for instance, can be as old as the organism, even up to more than a century, and must function for a lifetime. This remarkable age of neurons might be a major risk factor for neurodegenerative disorders such as Alzheimer’s disease. Crucial to comprehending these kinds of ailments is a deeper understanding of how nerve cells function over time and maintain control. This potentially opens doors to therapeutically counteract the aging processes of these specific cells.
The latest collaborative publication by Hetzer, Tomohisa Toda from the Friedrich-Alexander University Erlangen-Nürnberg (FAU), who is also associated with the Max Planck Center for Physics and Medicine, Erlangen, and colleagues, gives new insights into this underexplored field of intricate mechanisms. For the first time in mammals, the study shows that RNA — an essential group of molecules important for various biological processes inside the cell — can persist throughout life. The scientists identified specific RNAs with genome-protecting functions in the nuclei of nerve cells of mice that remain stable for two years, covering their entire lives. The findings, published in the journal Science, underpin the importance of long-lived key molecules for maintaining a cell’s function.
The inside of cells is a very dynamic place. Some components are constantly renewed and updated; others stay the same their whole lives. It is like a city in which the old buildings blend in with the new ones. DNA found in the nucleus — the city’s heart — for instance, is as old as the organism.
“DNA in our nerve cells is identical to DNA within the developing nerve cells in our mother’s womb,” explains Hetzer.
Unlike stable DNA, which is constantly being repaired, RNA, especially messenger RNA (mRNA), which forms proteins upon DNA’s information, is characterized by its transient nature. The cellular scope, however, extends beyond mRNA to a group of so-called non-coding RNAs. They do not turn into proteins; instead, they have specific duties to contribute to the overall organization and function of the cell. Intriguingly, their lifespan remained a mystery. Until now.
Hetzer and Co. set out to decipher that secret. Therefore, RNAs were labeled, i.e. “marked,” in the brains of newborn mice. “For this labeling, we used RNA analogs — structurally similar molecules — with little chemical hooks that click fluorescent molecules on the actual RNAs,” explains Hetzer. This assured efficient tracking of the molecules and powerful microscopic snapshots at any given time point in the mice’s lives.
“Surprisingly, our initial images revealed the presence of long-lived RNAs, in various cell types within the brain. We had to further dissect the data to identify the ones in the nerve cells,” Hetzer explains. “Fruitful collaboration with Toda’s lab enabled us to make sense of that chaos during brain mapping.”
Collaboratively, the researchers were able to focus solely on long-lived RNAs in neurons. They quantified the molecules’ concentration throughout a mouse’s life, examined their composition and analyzed their positions.
While humans have an average life expectancy of around 70 years, the typical lifespan of a mouse is 2.5 years. After one year, the concentration of long-lived RNAs was slightly reduced compared to newborns. However, even after two years, they remained detectable indicating a lifelong persistence of these molecules.
Additionally, the scientists proved long-lived RNAs’ prominent role in cellular longevity. They found out that long-lived RNAs in neurons consist of mRNAs and non-coding RNAs and accumulate near the heterochromatin — the densely packed region of the genome, typically homing inactive genes. Next they further investigated the function of these long-lived RNAs.
In molecular biology, the most effective approach to achieve this is by reducing the molecule of interest and observing its subsequent effects. “As their name and our previous experiments suggest, these long-lived RNAs are extremely stable,” says Hetzer. The scientists, therefore, employed an in vitro (outside a living organism) approach, using neuronal progenitor cells — stem cells with the capacity to give rise to neural cells, including neurons. The model system allowed them to effectively intervene with these long-lived RNAs. A lower amount of long-lived RNAs caused problems in the heterochromatin architecture and stability of genetic material, eventually affecting the cells’ viability. Thus, the important role of long-lived RNAs’ in cellular longevity was clarified.
The study highlights that long-lived RNAs may function in the lasting regulation of genome stability.
“Lifelong cellular maintenance during aging involves an extended life span of key molecules like the long-lived RNAs, we just identified,” Hetzer adds. The precise mechanism, however, remains unclear. “Together with unidentified proteins, long-lived RNAs likely form a stable structure that somehow interacts with the heterochromatin.”
Upcoming research projects in Hetzer’s lab are set on finding these missing links and understanding the biological characteristics of these long-lived RNAs.
Ancestral allele of DNA polymerase gamma modifies antiviral tolerance
by Kang Y, Hepojoki J, Maldonado RS, et al. in Nature
A multidisciplinary team of scientists led by University of Helsinki reports that a progressive neurodegenerative disease can be triggered by a viral infection. The mechanism relates to mitochondrial roles in antiviral defense mechanisms.
The scientists report that a specific gene variant affecting the mitochondria disturb cellular antiviral defense responses. The results implicate that viral infections can trigger and modify symptoms of neurological diseases in subjects carrying genetic sensitivity.
Why a disease manifests at a certain age, and what kind of triggers may be involved, are still open questions. Recent data indicate that mitochondria, the cellular centers of energy and nutrient metabolism, have new important roles in protecting cells from both internal and external stresses. Importantly, a novel role of mitochondria in strengthening the immune system has been recognized, but the relevance of these functions for human diseases has been unclear.
The current study shows that deficient mitochondrial functions in immune defense is connected to manifestation of brain diseases and sometimes also liver dysfunction. A multidisciplinary team led by academy professor Anu Suomalainen discovered that a genetic variant affecting the function of mitochondrial POLG enzyme delays detection of viral infection, leading to delayed severe inflammatory reaction damaging the brain and liver.
The POLG variant originates from a single individual dating back to Viking times and has spread to populations of European origin. Especially Northern European countries show high carrier frequencies: one in a hundred individuals in Finland and Norway. If a subject inherits the POLG-variant from both parents, a neurological disease, MIRAS (mitochondrial recessive ataxia syndrome), manifests. However, the ages of onset and manifestations of MIRAS are highly variable, raising the question whether the disease is triggered by additional factors.
Using a variable set of model systems, the team shows that the POLG variant leads to a weakened initial immune activation in response to viral infection, followed by a delayed, overactivated inflammation damaging the brain and liver. The scientists suggest that this mechanism explains why some MIRAS patients manifest in teenage with severe epilepsy, while some other patients with the same genetic background show disease signs years or even decades later, as motor coordination defects or Parkinson’s disease.
“Our results indicate that external factors, such as viral infections, can modify manifestation and age-of-onset of neurological diseases”, postdoctoral scientist Yilin Kang comments. “Identification of susceptibility factors and triggering mechanisms are valuable targets for new therapy developments. The current findings indicate the importance of new mitochondrial functions in maintaining brain health”.
A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals
by Jennings MV, Martínez-Magaña JJ, Courchesne-Krak NS, et al. in eBioMedicine.
A research group centered at the University of California San Diego School of Medicine has drilled deep into a dataset of over 3 million individuals compiled by the direct-to-consumer genetics company 23andMe, Inc., and found intriguing connections between genetic factors influencing alcohol consumption and their relationship with other disorders.
Sandra Sanchez-Roige, Ph.D., corresponding author and associate professor at UC San Diego School of Medicine Department of Psychiatry, explained that the study used genetic data to broadly classify individuals as being European, Latin American and African American. Such classifications “are needed to avoid a statistical genetics pitfall called population stratification,” noted co-author Abraham A. Palmer, Ph.D., professor and vice chair for basic research in the psychiatry department.
The researchers analyzed genetic data from the 3 million 23andMe research participants, focusing on three specific little snippets of DNA known as single-nucleotide polymorphisms, or SNPs. Sanchez-Roige explained that variants, or alleles, of these particular SNPs are “protective” against a variety of alcohol behaviors, from excessive alcohol drinking to alcohol use disorder.
One of the alcohol-protective variants they considered is very rare: the most prevalent among the three alleles found in the study showed up in 232 individuals of the 2,619,939 European cohort, 29 of the 446,646 Latin American cohort and in 7 of the 146,776 African American cohort; others are much more common. These variants affect how the body metabolizes ethanol — the intoxicating chemical in alcoholic beverages.
But the paper notes individuals with the alcohol-protective alleles also had worse health outcomes in certain areas: more lifetime tobacco use, more emotional eating, more Graves’ disease and hyperthyroidism. Individuals with the alcohol-protective alleles also reported totally unexpected differences, such as more malaria, more myopia and several cancers, particularly more skin cancer and lung cancer, and more migraine with aura.
Sanchez-Roige acknowledged that there is a chicken-and-egg aspect to their findings. For example: Cardiovascular disease is just one of a number of maladies known to be associated with alcohol consumption. “So is alcohol consumption leading to these conditions?” she asks. Palmer finishes the thought: “Or do these genetic differences influence traits like malaria and skin cancer in a manner that is independent of alcohol consumption?”
Sanchez-Roige said that such broad, hypothesis-free studies are only possible if researchers have access to very large sets of data. Many datasets, including the one used in the study, rely heavily on individuals with European ancestry.
“It is important to include individuals from different ancestral backgrounds in genetic studies because it provides a more complete understanding of the genetic basis of alcohol behaviors and other conditions, all of which contributes to a more inclusive and accurate understanding of human health,” she said. “The study of only one group of genetically similar individuals (for example, individuals of shared European ancestry) could worsen health disparities by aiding discoveries that will disproportionately benefit only that population.”
She said their study opens numerous doors for future research, chasing down possible connections between the alcohol-protective alleles and conditions that have no apparent connection with alcohol consumption.
“Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine,” Sanchez-Roige noted.
Ketogenic diet intervention on metabolic and psychiatric health in bipolar and schizophrenia: A pilot trial
by Sethi S, Wakeham D, Ketter T, Hooshmand F et al. in Psy. Res.
Cutting out the carbs could lessen the symptoms of bipolar disorder and schizophrenia, according to a new study. In a small pilot trial of 21 adults (16 with bipolar disorder, 5 with schizophrenia), researchers found that a 4-month-long low-carbohydrate, high-fat diet improved the majority of participants’ mental health scores. The participants also, on average, lost 10% of their body weight, lowered their blood pressure and improved their sleep and life satisfaction scores.
Many current medications for bipolar disorder and schizophrenia come with an increased risk of insulin resistance and obesity.
The ketogenic diet, on the other hand, can help dieters lose weight. It excludes common high-carb foods like bread, pasta, rice and cereals and promotes high-fat foods like cheese. In the world of medicine, it is sometimes recommended for people with epilepsy, as brain neurons fueled by ketones (a by-product of fat) appear to misfire less than neurons fueled by glucose (a by-product of carbohydrates).
Curious as to whether the diet could also benefit patients with bipolar disorder and schizophrenia — and reduce their levels of obesity — researchers at Stanford Medicine recruited 21 adults to try it for 4 months.
“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” said Shebani Sethi, an associate professor of psychiatry and behavioral sciences at Stanford Medicine. “We thought it would be worth exploring this treatment in psychiatric conditions.”
All participants had been diagnosed with one of the two mental health disorders and were either overweight or had a metabolic abnormality such as glucose intolerance.
After four months on the low-carb, mild-protein, high-fat diet, the participants were assessed to check their levels of mental health and obesity. A total of 14 participants were considered full-adherents to the diet (on the ketone diet more than 80% of the time), 6 were classified as semi-adherent (on the diet 60–80% of the time) and 1 was non-adherent (on the diet less than 50% of the time).
Initially, 29 % of the cohort met criteria for metabolic syndrome, a group of health problems that put a person at high risk of type 2 diabetes. After the four-month period, none of the participants met the criteria.
“We’re seeing huge changes,” said Sethi. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”
On average, the participants lost 10% of their body weight, reduced their waist circumference by 11% and had lower blood pressure, body mass indexes, levels of triglycerides, blood sugar and insulin resistance.
The benefits to the participants’ mental health scores were even more striking.
On average, the participants improved 31% on a standard psychiatrist rating of mental illness, known as the clinical global impressions scale. Around three-quarters of the group showed clinically meaningful improvement in overall mental health. The cohort also reported better sleep and greater life satisfaction.
“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”
Some of the testimonies taken from the participants speak for themselves.
“It can honestly save a lot of lives, it saved mine,” said one participant. “I would not be here today if it wasn’t for Keto. It’s helped a lot with my mood Stabilization.” “I can tell you that I have never felt better than I have since using ketosis,” said another, “it worked far better than the lamotrigine [a typical bipolar medication] ever did.”
Sethi and her colleagues say the findings of their pilot study should encourage more research into the growing field of “metabolic psychiatry”, given the proportion of mental health patients seeking alternative treatment.
“Many of my patients suffer from both illnesses, so my desire was to see if metabolic interventions could help them,” she said. “They are seeking more help. They are looking to just feel better.”
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