Carbon Chemist

Tag: Calcium

  • How cell types and location influence Parkinson’s disease

    How cell types and location influence Parkinson’s disease

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    In a recent study published in Cell Reports, researchers conducted a single-cell spatial transcriptome analysis on murine brain expression in age and disease using a Parkinson’s disease (PD) transgenic model, focusing on dopaminergic neurons (DA) spanning 29 cell types.

    Study: Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease. Image Credit: solarseven/Shutterstock.comStudy: Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease. Image Credit: solarseven/Shutterstock.com

    Background

    The spatially structured brain contains various cells, each with a distinct purpose. PD is a neurodegenerative condition characterized by DA loss and alpha-synuclein buildup due to overexpression via locus multiplication.

    Single-cell ribonucleic acid sequencing (RNS-seq) has improved the knowledge of cell-based expression in organs such as the brain, but current methods fail to attain high-throughput resolution. Fluorescent in situ hybridization (FISH) technologies provide higher sensitivity at an individual level.

    About the study

    In the present study, researchers performed single-cell spatial transcriptomic and translatomic profiling of DA to find markers for healthy and aged cells.

    The researchers crossed Rosa26fsTRAP::DATIREScre (DAT-TRAP) mice with SNCA-OVX mice to enable DA messenger RNA (mRNA) capture in a PD model.

    The mice were aged to 18 months to assess the influence of human ⍺-synuclein overexpression and aging on dopaminergic neuron genetic expression and study the effect of healthy and Parkinsonian aging.

    The researchers created a single-cell-level spatial transcriptomic map of gene expression in the adult mouse brain and a high-fidelity translatome-level profile of DA neuron expression.

    They analyzed stereo-seq arrays with special transcript maps. They converted the transcript expression maps to segmented individual cells, identifying 29 types of cells, including astrocytes and inhibitory cortical neurons, in 18 brain slices.

    The team filtered the segmented cells by transcriptome size and complexity and analyzed spatially distinct cortex, hippocampus, and thalamus populations. They also examined the ventral midbrain and striatum to enrich transcripts confined to the cell body and putative axon.

    They used data from gene enrichment and genome-wide association studies (GWAS) to identify potential disease-causing genes.

    They evaluated each cell’s location and compared DA neuronal gene expression in various cells.

    The researchers examined enhanced green fluorescent protein (eGFP)-tagged ribosomes in DAT-expressing cells and confirmed eGFP colocalization with tyrosine hydroxylase (TH), a DA neuronal marker.

    They split cells from stereo-seq brain slices, filtering them based on detected genes, and performed Uniform Manifold Approximation and Projection (UMAP) analysis.

    They also performed short- and long-read RNA sequencing of the translating mRNA collected by TRAP and used stereo-sequencing and TRAP data to rank prospective genes for inquiry into sporadic PD.

    The researchers demonstrated specific enrichment of DA marker genes and depletion of marker genes of other neighboring cell types in DAT-TRAP mRNA.

    They confirmed specific calcium-sensing receptor (CASR) protein expression in mouse ventral midbrain neurons and investigated CASR expression in human-induced pluripotent stem cell-derived DA neurons. They also examined age-related gene variations in cells revealed by stereo-seq.

    Results

    The team studied PD in young and aged brains to identify genes having spatially varying expression in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and particular markers such as copine-7 (Cpne7) and Solute carrier family 10 member 4 (Slc10a4) genes.

    They also detected splice variants unique to DA. They demonstrated ways of using TRAP and stereo-sequencing expression specificity measurements to identify potentially relevant genes from GWAS areas, indicating that CASR regulates intracellular DA neuronal calcium.

    The findings demonstrated substantia nigra-specific DA neuronal loss and increased microglial activation with age. They highlighted aging- and disease-associated genetic alterations in various cells, including dopaminergic neurons, across many PD-related pathways.

    Stereo-seq detected expression alterations caused by aging and illness across different cell types, loss of nigral DA neurons, and the neuroinflammatory expansion of microglia.

    Pathway enrichment research revealed that various biological processes were altered, including axon ensheathment, synaptic transmission modulation, intracellular calcium ion homeostasis, and catecholamine secretion control.

    The team extracted 355,307 transcriptomes of high quality with spatial coordinate details from 18 murine brains, identifying a total of 14,494 genes.

    They observed synaptosomal-associated protein, 25kDa (Snap25) expression, and structured localization in places like the thalamus or hippocampus differentiated neurons from glia.

    They also examined neuronal cells in the CA1 region, CA3 region, subiculum, and dentate gyrus in the hippocampus region or gamma-aminobutyric acid (GABA)-releasing nuclei in the midbrain.  

    Marker expression enabled oligodendrocyte, astrocyte, microglia, and erythrocyte identification. In DAT-TRAP samples, classical markers of dopaminergic neurons showed significant enrichment, whereas those of other cell types decreased in the ventral midbrain.

    Conclusion

    Overall, the study identified 29 unique brain cell types by examining variations in spatial gene expression linked to aging and illness. The stereo-seq data indicated differences in transcript use across more than a thousand genes.

    There were 817 occurrences of alternative splicing, suggesting that more genes were being translated than gene-level count data showed. The study also discovered an age-dependent drop in SN DA neuron cell number, which supports earlier findings.

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  • Novel technique could transform the treatment landscape for brain disorders

    Novel technique could transform the treatment landscape for brain disorders

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    The human brain’s adaptability to internal and external changes, known as neural plasticity, forms the foundation for understanding cognitive functions like memory and learning, as well as various neurological disorders. New research conducted by a team led by Dr. PARK Joo Min of the Center for Cognition and Sociality within the Institute for Basic Science (IBS) unveils a novel technique that could transform the treatment landscape for brain disorders. The team developed a non-invasive brain stimulation method called Patterned Low-Intensity Low-Frequency Ultrasound (LILFUS), which holds tremendous potential for inducing long-lasting changes in brain function.

    Traditionally, magnetic and electrical brain stimulation methods have been used to modulate brain function. However, these methods come with inherent limitations that restrict their spatial resolution and penetration depth, making it challenging to precisely stimulate specific brain regions with optimal efficacy. More invasive methods, such as those that require surgical procedures, exhibit superior control and therapeutic effects for specific deep brain stimulation, but they come with risks such as tissue damage, inflammation, and infection. These limitations have fueled the search for alternative approaches that can overcome these constraints and provide more efficient and precise modulation of brain function.

    In the latest study unveiled by the IBS, researchers used ultrasound to enable precise stimulation of specific brain areas. Unlike electromagnetic waves, ultrasound has the advantage of being able to penetrate deep into the brain tissues. The researchers discovered that ultrasound stimulation can modulate neural plasticity – the brain’s ability to rewire itself – through the activation of key molecular pathways. Specifically, the study pinpointed the ultrasound’s effect on mechanosensitive calcium channels in astrocytes, which controls the cells’ ability to uptake calcium and release neurotransmitters.

    LILFUS was designed based on specific ultrasound parameters that mimic the brainwave patterns of theta (5 Hz) and gamma (30 Hz) oscillations observed during learning and memory processes. The new tool allowed the researchers to either activate or deactivate specific brain regions at will – intermittent delivery of the ultrasound was found to induce long-term potentiation effects, while continuous patterns resulted in long-term depression effects.

    One of the most promising aspects of this new technology is its ability to facilitate the acquisition of new motor skills. When the researchers delivered ultrasound stimulation to the cerebral motor cortex in mice, they observed significant improvements in motor skill learning and the ability to retrieve food. Interestingly, researchers were even able to change the forelimb preference of the mice. This suggests potential applications in rehabilitation therapies for stroke survivors and individuals with motor impairments.

    The implications of this research extend far beyond motor function. It may be used to treat conditions such as depression, where altered brain excitability and plasticity are prominent features. With further exploration, LILFUS could be adapted for various brain stimulation protocols, offering hope for various conditions ranging from sensory impairments to cognitive disorders.

    This study has not only developed a new and safe neural regulation technology with long-lasting effects but has also uncovered the molecular mechanism changes involved in brainwave-patterned ultrasound neural regulation. We plan to continue follow-up studies to apply this technology for the treatment of brain disorders related to abnormal brain excitation and inhibition and for the enhancement of cognitive functions.”


    Dr. Park Joo Min of the Center for Cognition and Sociality, Institute for Basic Science

    Source:

    Institute for Basic Science

    Journal reference:

    Kim, H-J., et al. (2024) Long-lasting forms of plasticity through patterned ultrasound-induced brainwave entrainment. Science Advances. doi.org/10.1126/sciadv.adk3198.

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  • Study reveals unexpected link between cell membrane damage and cellular senescence

    Study reveals unexpected link between cell membrane damage and cellular senescence

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    Our cells are surrounded by a fragile membrane that’s only 5 nanometers thick, 1/20 of a soap bubble. Cells are easily damaged by physiological activities, including muscle contraction and tissue injury. To cope with such damage, cells are equipped with mechanisms that can repair membrane damage to a certain degree.

    Mechanical damage to the cell membrane was previously believed to trigger two simple cellular outcomes: recovery or death. In this study, however, the researchers uncovered a third outcome – cellular senescence. 

    “When I started this project, I simply aimed to understand the repair mechanisms of damaged cell membrane,” recalls Professor Keiko Kono, head of the Membranology unit and senior author of this study, which involved multiple members from the unit, including Kojiro Suda, Yohsuke Moriyama, Nurhanani Razali and colleagues. “Unexpectedly, we ended up discovering that cell membrane damage, in a sense, switches cell fate.”

    The key to determining cell fate is the extent of damage and subsequent calcium ion influx. The thin cell membrane damage can be easily repaired, allowing the cells to continue cell division without any trouble. The highest level of cell membrane damage induces cell death. However, a middle level of cell membrane damage turns the cells into senescent cells several days later, even though membrane resealing seems successful. 

    Cancer cells divide unlimitedly. In contrast, non-cancerous normal cells have a limited capacity for cell division – around 50 times before division is irreversibly stopped, and the cells enter a state known as cellular senescence. Senescent cells are still metabolically active, but unlike young and healthy cells, they produce various secretory proteins that upregulate immune responses in both nearby tissues and distant organs. This mechanism can induce both beneficial and detrimental changes in our body, including acceleration of wound healing, cancer promotion, and aging. During the last decade, numerous studies have reported that senescent cells exist in animal bodies, including humans, and that the removal of senescent cells can rejuvenate body functions in experimental animals. However, the cause of cell senescence in the human body remains a controversial topic.

    The gene expression profile and bioinformatics suggested that cell membrane damage explains the origin of senescent cells in our bodies, specifically the ones near damaged tissues.”


    Professor Keiko Kono, Senior Author

    The best-established inducer of cellular senescence is repeated cell division. Many other stresses also induce cellular senescence in a laboratory setting, such as DNA damage, oncogene activation, and epigenetic changes. The long-standing dogma in the research field was that various stresses induce cellular senescence ultimately via the activation of DNA damage response. However, the authors uncovered that cell membrane damage induces cellular senescence via a different mechanism that involves calcium ions and the tumor suppressor gene p53. These findings may contribute to develop a strategy to achieve healthy longevity in the future.

    Source:

    Okinawa Institute of Science and Technology (OIST) Graduate University

    Journal reference:

    Suda, K., et al. (2024). Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts. Nature Aging. doi.org/10.1038/s43587-024-00575-6.

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  • Ultrahigh-spatial-resolution PCD-CT improves assessment of coronary artery disease

    Ultrahigh-spatial-resolution PCD-CT improves assessment of coronary artery disease

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    Ultrahigh-spatial-resolution photon-counting detector CT improved assessment of coronary artery disease (CAD), allowing for reclassification to a lower disease category in 54% of patients, according to a new study published today in Radiology, a journal of the Radiological Society of North America (RSNA). The technology has the potential to improve patient management and reduce unnecessary interventions.

    Coronary CT angiography is a first-line test in the assessment of coronary artery disease. However, its diagnostic value is limited in patients with severe calcifications, or calcium buildup in the plaque of the coronary arteries.

    Ultrahigh-spatial-resolution photon-counting detector CT (PCD-CT) improves image quality compared to conventional CT. Additionally, it provides better spatial resolution, or the ability to differentiate two adjacent structures as being distinct from one another.

    Our study provides a glimpse into the potential impact of performing coronary CT angiography using ultrahigh spatial resolution technology on risk reclassification and recommended downstream testing.” 

    Tilman Emrich, M.D., study co-author, attending radiologist at the University Medical Center Mainz in Germany, and assistant professor of radiology at the Medical University of South Carolina in Charleston

    For the study, researchers evaluated coronary stenoses, or narrowing in the coronary arteries, in a vessel phantom (in-vitro) containing two different stenosis grades (25%, 50%), and retrospectively in 114 patients (in-vivo) who underwent ultrahigh-spatial-resolution cardiac PCD-CT for the evaluation of coronary artery disease. In-vitro values were compared to the phantom’s manufacturer specifications, and patient results were assessed regarding effects on coronary artery disease reporting and data system reclassification (CAD-RADS).

    “The study used a combination of artificial vessel models and real-world patient data,” Dr. Emrich said. “It simulated three types of reconstructions from a single PCD-CT scan, resembling conventional CT, high-resolution, and ultrahigh-spatial-resolution scans. Observers evaluated the severity of stenosis and generated CAD-RADS classifications, guiding further patient management decisions.”

    In-vitro results demonstrated a reduced overestimation of the stenosis by ultrahigh-spatial-resolution scans by reducing the adverse effects of the calcifications on the image.

    Results from the patients with suspected or diagnosed coronary artery disease confirmed a lower median degree of stenosis for calcified plaques (29% vs. 42%) with ultrahigh-spatial-resolution PCD-CT compared to standard CT. Ultrahigh-spatial-resolution often led to patients being reclassified to a lower CAD-RADS category. Of the 114 patients, 54% were given a lower CAD-RADS classification than they were originally assigned. The researchers found in-vitro quantification of the 193 coronary CT angiography-based stenoses was also more accurate using ultrahigh-spatial-resolution than standard resolution.

    “We found that ultrahigh-spatial-resolution reconstructions resulted in significant changes in recommendations for over 50% of patients,” Dr. Emrich said. “The impact was particularly notable in cases with calcified plaques, where ultrahigh-spatial-resolution reduced the overestimation of stenosis.”

    Dr. Emrich explained that ultrahigh-spatial-resolution may address the current limitations of conventional cardiac CT angiography by reducing the overestimation of stenosis due to calcium blooming, an effect which can cause small, high-density structures-;such as calcifications-;to appear larger than their true size.

    “This could significantly alter recommendations for downstream testing, potentially leading to a reduction of unnecessary procedures (and their potential complications) and reduced healthcare costs,” he said.

    No substantial benefits of ultrahigh-spatial-resolution were observed for mixed and non-calcified plaques.

    “It is important to note that these findings are from a simulation study, and further validation is needed in real-world comparisons,” Dr. Emrich said.

    “Ultrahigh-Spatial-Resolution Photon-counting Detector CT Angiography of Coronary Artery Disease for Stenosis Assessment.” Collaborating with Dr. Emrich were Moritz C. Halfmann, M.D., Stefanie Bockius, M.D., Michaela Hell, M.D., U. Joseph Schoepf, M.D., Gerald S. Laux, M.D., Larissa Kavermann, M.D., Dirk Graafen, M.D., Tomasso Gori, M.D., Ph.D., Yang Yang, M.D., Roman Klöckner, M.D., Pál Maurovich-Horvat, M.D., Ph.D., Jens Ricke, M.D., Lukas Müller, M.D., Akos Varga-Szemes, M.D., Ph.D., and Nicola Fink, M.D.

    Source:

     Radiological Society of North America

    Journal reference:

    Halfmann, M. C., et al. (2024) Ultrahigh-Spatial-Resolution Photon-counting Detector CT Angiography of Coronary Artery Disease for Stenosis Assessment. Radiology. doi.org/10.1148/radiol.231956.

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  • Study provides evidence that antidepressant use in pregnancy affects child’s brain development

    Study provides evidence that antidepressant use in pregnancy affects child’s brain development

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    The prefrontal cortex (PFC) is an important brain region with respect to behavioral regulation. Aberrations in serotonin (5-HT) during early development have been reported to be associated with behavioral dysregulations over the long term, but how this works is still unclear.

    Study: Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Image Credit: fizkes/Shutterstock.com
    Study: Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Image Credit: fizkes/Shutterstock.com

    A new study published in Nature Communications explored synapse maturation in the PFC of mice when exposed to 5-HT, shedding light on the link between the chemical and future behavioral changes.

    Researchers from the University of Colorado Anschutz Medical Campus demonstrated a direct link between antidepressant use during pregnancy, particularly fluoxetine found in medications like Prozac and Sarafem, and altered development of the prefrontal cortex in children, as well as subsequent mental health risks.

    Background

    The brain has over a billion neurons, with equal numbers of other cells linked in intricate and interwoven networks. These require exquisitely precise chemical regulation to develop correctly so as to provide the substrate for communication between themselves and the formation of neuronal pathways.

    5-HT is among the first neurochemicals to be detected, being found at peak levels two years after birth in humans. In mice, it peaks during the first week after birth. This period coincides with the time when excitatory synapses mature following experience-driven activity.

    Various causes of alteration in 5-HT are known, including maternal malnutrition, maternal abuse, varying levels of dietary tryptophan (the substrate for 5-HT formation), and the presence of chemicals that regulate the uptake or degradation of 5-HT.

    An example of the latter is the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). These can readily cross the placenta or enter breast milk, becoming available to the offspring during a critical period of brain development.

    Such imbalances in 5-HT levels at this period have been linked to a higher chance of neurodevelopmental disorders, including autism spectrum disorder (ASD), as well as permanent behavioral changes. The PFC is involved in cognitive processes that facilitate social interaction and is lavishly supplied with neurons that release 5-HT.

    Excitatory synapses are fundamental to the formation of neural circuits. They need to mature and stabilize for this to happen, with the primary sites of action of the neurotransmitter released at the synapse being the dendritic spines of the post-synaptic neuron. These bear multiple receptor types for 5-HT, with 5-HT2A and 5-HT7 being especially abundant in early infancy.

    When these are activated, excitatory cascades are activated via the coupled Gαq proteins. Higher levels of 5-HT signaling increase the dendritic spine plasticity. The current study looked at targeted 5-HT signaling at the level of neural circuits and individual excitatory synapses, seeking to identify the mode of regulation. 

    What did the study show?

    The scientists found that 5-HT is crucial for the normal development of excitatory synapses on the pyramidal neurons within layer 2/3 of the PFC during early development. With 5-HT inhibition, both spine density and maturation were reduced significantly within the PFC, though spine size remained intact. The converse was also true, with increased density, especially of large spines, but with normal size and morphology.

    Apart from these anatomical changes, 5-HT signaling causes structural long-term potentiation of dendritic spines on these neurons during this developmental window independent of excitatory stimulation. This effect, namely, the enlargement of small and medium spines, did not appear to depend on the activity of glutamate.

    Not only was it specific for the pattern of 5-HT stimulation, but also it was not observed at later stages or in pyramidal neurons. In addition, it occurred only in the presence of post-synaptic 5-HT2A and 5-HT7 signaling. This suggests that the underlying mechanism is 5-HT7 receptor-mediated influx of extracellular calcium ions, leading to 5-HT2A receptor-induced activation of PKC.

    Functional long-term potentiation of these receptors was also observed in response to 5-HT release, again via 5-HT2A and 5-HT7 receptor signaling. That is, stronger post-synaptic excitatory currents were measured following 5-HTergic stimulation.

    Individual dendritic spines newly formed on these neurons in the PFC were more likely to survive, indicating greater long-term stabilization following Gαs coupled 5-HT7 receptor signaling. This is important as it leads to increased spine density. Again, this effect, linked to long-term potentiation, is independent of glutamate release or structural potentiation and does not appear to occur with 5-HT2A receptor stimulation.

    Significantly, early research shows a risk of behavioral deficits and neurodevelopmental disorders with early fluoxetine exposure. In the present study, the use of fluoxetine, an SSRI that increases 5-HT levels in the synaptic cleft in younger but not older pups, led to increased spine density but not spine size. This was mediated by 5-HT2AR and 5-HT7R signaling in the PFC.

    What are the implications?

    The findings of this study indicate that 5-HT signaling plays a key role in excitatory synapse maturation during early development of the PFC circuits, regulating spine maturation and function. The effect is structural and functional potentiation of excitatory synapses of layer 2/3 pyramidal neurons in the PFC at a specific age and with a specific pattern of stimulation.

    The results also suggest a direct effect of 5-HT on maturation rather than via changes in excitability, but further work is required to rule out glutamatergic involvement in synaptic plasticity secondary to 5-HT signaling completely.

    The researchers propose that nascent spines are stabilized by 5-HT7 receptor activation via voltage-gated calcium channel opening, leading to the entry of calcium into the neuron. However, as they mature, both 5-HT7 and 5-HT2A receptors lead to synapse maturation via PKC activation, which further enhances extracellular calcium ion influx.

    Moreover, 5-HT receptor-mediated synaptic plasticity occurs in the first two weeks in mice. Further research will be required to demonstrate what receptor classes are involved at later stages. Again, increased excitatory post-synaptic current strength without spine size alterations needs to be explained.

    These findings may help treat patients who have been exposed to drugs like fluoxetine during early development, as this is a commonly prescribed drug during pregnancy. Moreover, it may be possible to treat individuals with aberrations in 5-HT receptor-mediated plasticity during this key period by selective inhibition of 5-HT receptors in certain brain regions or certain types of neurons.

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  • New treatment target found for CDKL5 deficiency disorder

    New treatment target found for CDKL5 deficiency disorder

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    Scientists at the Francis Crick Institute have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. 

    CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function.

    Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme’s activity to compensate for the loss of CDKL5. 

    In research published today in Molecular Psychiatry, the scientists studied mice that don’t make the CDKL5 enzyme. These mice show similar symptoms to people with CDD like impaired learning or social interaction. 

    The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn’t produced. 

    Interestingly, even in mice that don’t produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

    By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.

    The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining <5% from another enzyme yet to be identified. 

    Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development. 

    CDD is a devastating condition that impacts young children from birth, and we don’t know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we’ve identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse.”


    Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory, The Francis Crick Institute

    The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD. 

    Margaux Silvestre, former PhD student at the Crick and now postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: “Our discoveries offer fresh insights into the expression and regulation of CDKL5 in the brain. Moreover, the identification of CDKL2 as a potential compensatory enzyme provides hope for uncovering better treatments that could truly make a difference in the lives of the children with this devastating condition. This research owes its success to all the authors involved in the publication but also the unwavering support we received from the technical teams at the Crick – a big shoutout to them!”

    The research was funded by the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD.

    Source:

    The Francis Crick Institute

    Journal reference:

    Silvestre, M., et al. (2024). Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry. doi.org/10.1038/s41380-024-02434-7.

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  • Study reveals impact of lantibiotic preservatives on gut microbiome

    Study reveals impact of lantibiotic preservatives on gut microbiome

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    Food manufacturers often add preservatives to food products to keep them fresh. A primary purpose of these preservatives is to kill microbes that could break down and otherwise spoil the food. Common additives like sugar, salt, vinegar and alcohol have been used as preservatives for centuries, but modern-day food labels now reveal more unfamiliar ingredients such as sodium benzoate, calcium propionate, and potassium sorbate.

    Bacteria produce chemicals called bacteriocins to kill microbial competitors. These chemicals can serve as natural preservatives by killing potentially dangerous pathogens in food. Lanthipeptides, a class of bacteriocins with especially potent antimicrobial properties, are widely used by the food industry and have become known as “lantibiotics” (a scientific portmanteau of lanthipeptide and antibiotics).

    Despite their widespread use, however, little is known about how these lantibiotics affect the gut microbiomes of people who consume them in food. Microbes in the gut live in a delicate balance, and commensal bacteria provide important benefits to the body by breaking down nutrients, producing metabolites, and-;importantly-;protecting against pathogens. If too many commensals are indiscriminately killed off by antimicrobial food preservatives, opportunistic pathogenic bacteria might take their place and wreak havoc-;a result no better than eating contaminated food in the first place.

    Effects on good and bad bacteria

    A new study published in ACS Chemical Biology by scientists from the University of Chicago found that one of the most common classes of lantibiotics has potent effects both against pathogens and against the commensal gut bacteria that keep us healthy.

    Nisin is a popular lantibiotic used in everything from beer and sausage to cheese and dipping sauces. It is produced by bacteria that live in the mammary glands of cows, but microbes in the human gut produce similar lantibiotics too. Zhenrun “Jerry” Zhang, PhD, a postdoctoral scholar in the lab of Eric Pamer, MD, the Donald F. Steiner Professor of Medicine and Director of the Duchossois Family Institute at UChicago, wanted to study the impact of such naturally-produced lantibiotics on commensal gut bacteria.

    Nisin is, in essence, an antibiotic that has been added to our food for a long time, but how it might impact our gut microbes is not well studied. Even though it might be very effective in preventing food contamination, it might also have a greater impact on our human gut microbes.”


    Zhenrun “Jerry” Zhang, PhD, postdoctoral scholar

    He and his colleagues mined a public database of human gut bacteria genomes and identified genes for producing six different gut-derived lantibiotics that closely resemble nisin, four of which were new. Then, in collaboration with Wilfred A. van der Donk, PhD, the Richard E. Heckert Endowed Chair in Chemistry at the University of Illinois Urbana-Champaign, they produced versions of these lantibiotics to test their effects on both pathogens and commensal gut bacteria. The researchers found that while the different lantibiotics had varying effects, they killed pathogens and commensal bacteria alike.

    “This study is one of the first to show that gut commensals are susceptible to lantibiotics, and are sometimes more sensitive than pathogens,” Zhang said. “With the levels of lantibiotics currently present in food, it’s very probable that they might impact our gut health as well.”

    Harnessing the power of lantibiotics

    Zhang and his team also studied the structure of peptides in the lantibiotics to better understand their activity, in the interest of learning how to use their antimicrobial properties for good. For example, in another study, the Pamer lab showed that a consortium of four microbes, including one that produces lantibiotics, help protect mice against antibiotic-resistant Enterococcus infections. They are also studying the prevalence of lantibiotic-resistant genes across different populations of people to better understand how such bacteria can colonize the gut under different conditions and diets.

    “It seems that lantibiotics and lantibiotic-producing bacteria are not always good for health, so we are looking for ways to counter the potential bad influence while taking advantage of their more beneficial antimicrobial properties,” Zhang said.

    Source:

    Journal reference:

    Zhang, Z. J., et al. (2024). Activity of Gut-Derived Nisin-like Lantibiotics against Human Gut Pathogens and Commensals. ACS Chemical Biology. doi.org/10.1021/acschembio.3c00577.

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  • Is there an association between vitamin D, immunocompetence, and aging?

    Is there an association between vitamin D, immunocompetence, and aging?

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    In a recent review published in the journal Nutrients, researchers explored the role of an individual’s immunocompetence in the responsiveness to vitamin D.

    They discussed the modulation of immunocompetence via the epigenetic programming function of the vitamin D receptor (VDR) and its ligand and highlighted the impact of aging on immunocompetence.

    Study: Vitamin D and Aging: Central Role of Immunocompetence. Image Credit: Iryna Imago/Shutterstock.comStudy: Vitamin D and Aging: Central Role of Immunocompetence. Image Credit: Iryna Imago/Shutterstock.com

    Background

    Vitamin D plays a crucial role in bone health by regulating calcium homeostasis and preventing conditions like rickets and osteomalacia. However, its influence on immunity extends beyond this function.

    Vitamin D deficiency, linked to modern lifestyle factors like limited sun exposure, affects the endogenous production of active vitamin D metabolites.

    The inactive vitamin D3 is converted to active 1,25(OH)2D3 in the liver and kidneys, which acts as a hormone and affects various tissues. Notably, various cells, including those of the innate immune system, can produce 1,25(OH)2D3 locally, contributing to auto- and paracrine effects. This compound acts as a ligand of high affinity for VDR, regulating the expression of numerous genes.

    The vitamin D status, indicated by serum 25(OH)D3 levels, categorizes individuals into deficient, insufficient, or sufficient groups. Vitamin D responsiveness varies among people due to genetic and epigenetic factors influencing molecular responses.

    Low responders, constituting about 25% of the population, may have increased susceptibility to diseases related to compromised immunity. The VDR-based modulation of immunocompetence may contribute to aging and reduce the risk of age-related diseases.

    The present review offers insights into the immunomodulatory functions of vitamin D and its impact on various health aspects beyond bone metabolism.

    Vitamin D signaling

    VDR binds specifically to genomic DNA, recognizing the motif RGKTSA. In complex with retinoid X receptor (RXR), VDR preferentially binds to direct repeat sequences in the euchromatin. Various “pioneer factors” facilitate VDR in opening chromatin, which is crucial for efficient binding.

    Chromatin accessibility and VDR binding can be assessed using next-generation sequencing technologies, including ChIP-seq (chromatin immunoprecipitation sequencing) and ATAC-seq (assay for transposase-accessible chromatin using sequencing), especially in peripheral blood mononuclear cells.

    Genomic regions of vitamin D target genes demonstrate changes in chromatin accessibility and VDR binding after vitamin D3 supplementation.

    Enhancers and transcription start site regions, even at a considerable linear distance, can interact via DNA looping within the same topologically associating domain, influencing gene expression.

    VDR’s genomic actions involve protein-protein interactions with the Mediator complex and RNA polymerase II, influencing transcription. Vitamin D also exerts epigenomic effects, altering DNA methylation, histone modifications, and chromatin organization, dynamically shaping the cell’s epigenetic landscape.

    These genomic and epigenomic effects contribute to vitamin D’s modulatory role in hematopoiesis and immunocompetence, affecting human immune cells both in vitro and in vivo.

    Epigenetic programming of immune cells

    Throughout embryogenesis and adult cellular differentiation, stem and progenitor cells undergo epigenetic programming, determining the function of terminally differentiated cells. 1,25(OH)2D3 plays a crucial role in this process, influencing hematopoiesis and the differentiation of immune cells.

    Hematopoietic stem cells (HSCs) differentiate into various blood and immune cell types, and 1,25(OH)2D3 regulates embryonic HSC numbers.

    Various transcription factors influenced by vitamin D drive the differentiation of myeloid progenitor cells into granulocytes and monocytes. Vitamin D is also the differentiation of monocytes into dendritic cells and macrophages.

    Epigenetic programming by vitamin D contributes to innate immune cell adaptation, modulating responses to infections, inflammation, and diseases.

    Variability in vitamin D status and response index among individuals affects the epigenetic programming of monocytes and derived cells, emphasizing the potential of optimized vitamin D3 supplementation for supporting proper immune cell epigenetics and overall immunocompetence. However, further research is needed to validate this concept fully.

    Decline in immunocompetence during aging

    Aging involves accumulating molecular damage, resulting in cellular dysfunction and weakened organs. Immunocompetence, crucial for appropriate immune responses, declines with age, leading to increased susceptibility to infections and diseases.

    The thymus atrophies, diminishing the production of T-cells, and “inflammaging” ensues. However, interindividual differences exist, and some individuals may display relatively higher immunocompetence.

    Lower immunocompetence correlates with accelerated aging and heightened disease risks. Vitamin D sufficiency may protect against cancers by preserving immunocompetence.

    Adequate vitamin D levels could stabilize immune resilience, safeguard against diseases, and contribute to healthy aging by mitigating various hallmarks of aging, including inflammation and cellular stress.

    Conclusion

    In conclusion, the active form of vitamin D plays a crucial role in modulating the epigenome of immune cells, particularly in monocytes.

    The observed associations between vitamin D deficiency, increased disease risk, and accelerated aging may be attributed to diminished immunocompetence.

    Considering individual responsiveness, a precautionary daily vitamin D3 dose of 1 µg (40 IU)/kg body mass is suggested, exceeding general recommendations but staying within safe limits to strengthen immunocompetence. The researchers emphasize personalized vitamin D supplementation to safeguard against prevalent diseases and promote healthy aging.

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