Category: 8. Health
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Rise in dengue fever outbreaks across the Pacific driven by the climate crisis, experts say | Pacific islands
The climate crisis is driving a sharp rise in dengue fever cases across the Pacific islands, experts say, as infections hit their highest level in a decade and several countries declare emergencies.
Pacific Island countries and territories have reported 16,502 confirmed cases and 17 deaths since the start of 2025, according to the Pacific Syndromic Surveillance System (PSSS), which collaborates with the World Health Organization (WHO) and other agencies. Infections across the region are at the highest level since 2016, the WHO said. Fiji, Samoa and Tonga are among the worst affected.
Dr Paula Vivili, deputy director general of the Pacific Community (SPC) said historically dengue outbreaks were seasonal.
“However, due to climate change, transmission seasons are lengthening, and some areas are experiencing year-round dengue risk,” Vivili said.
Dengue fever, a viral illness spread by Aedes mosquitoes, causes high fever, severe headache, joint and muscle pain, rash, and in severe cases, can be fatal. Rising temperatures, rainfall and increased humidity are creating ideal breeding conditions for Aedes mosquitoes, even in areas previously unsuitable for transmission.
“Dengue is one of the first real disease-related phenomena that we can lay at the foot of climate change,” said Dr Joel Kaufman, epidemiologist and director of the Center for Exposures, Diseases, Genomics and Environment at the University of Washington.
“Rainfall raises the waterline over mosquito eggs laid just above the surface, which then hatch – that’s part of the natural breeding cycle. Heavy rains can also increase stagnant water sources, creating more opportunities for mosquitoes to breed,” said Kaufman.
Kaufman warned these outbreaks point to a wider public health challenge.
“It is in the vanguard of what will certainly be many types of human disease that become more common and more serious as the planet warms.”
Since declaring an outbreak in April, Samoa has confirmed six dengue-related deaths, including two siblings, and more than 5,600 cases. This year Fiji has recorded eight deaths and 10,969 cases. Tonga has reported over 800 cases and three deaths, since declaring an outbreak in February.
These outbreaks underscore the region’s vulnerability to climate-sensitive diseases, which are expected to intensify as global temperatures rise.
Pacific Island countries produce just 0.03% of global greenhouse gas emissions, according to the Intergovernmental Panel on Climate Change (IPCC), but face some of the most severe climate-related health threats, including vector-borne diseases.
Recent months have brought extreme rainfall to parts of the Pacific including Palau, Papua New Guinea and Solomon Islands, while severe drought has gripped parts of the Marshall Islands, Papua New Guinea, Nauru and Fiji, according to the New Zealand National Institute of Water and Atmospheric Research (NIWA). Forecasts show these contrasts will continue into October.
Although higher rainfall has been attributed to ideal conditions for mosquito breeding, Kaufman said that extreme weather events can also increase transmission of mosquito-borne diseases. Seriously dry or very dry conditions were recorded across large parts of the Pacific in the first half of the year, according to NIWA.
“We might have thought the dryness would reduce mosquito-borne infections, but it seems that’s not what happens. Instead, there’s an acceleration of transmission.”
Across the Pacific, national responses have varied. Samoa, Cook Islands and American Samoa have declared emergencies. The Cook Islands has conducted island-wide clean-ups, intensified surveillance and targeted spraying. Tonga has worked with the WHO to bolster its outbreak response in its worst-hit islands, while Tuvalu has turned to social media and health campaigns to promote preventive measures. Samoa has held school clean-ups and boosted public health messaging. New Zealand has sent a clinical team and NZ$300,000 ($178,000) worth of medical supplies to Samoa, alongside on-the-ground personnel and ongoing coordination with Samoan health officials.
But experts say these measures are being undermined by inadequate surveillance.
“Current disease surveillance systems are rarely sufficient to manage dengue, as evidenced by the continual growth of dengue in the region, and more generally globally,” said Dr Bobby Reiner, disease ecologist at the Institute for Health Metrics and Evaluation at the University of Washington.
Mosquito control tools are methods used to reduce the population of Aedes mosquitoes that spread dengue, such as removing breeding sites, applying larvicides, or spraying insecticides. They can also include biological controls, personal protection measures, and community clean-up campaigns to prevent mosquito bites and transmission.
Still, Reiner said many mosquito control tools have never been proven to reduce transmission, with most responses reactive and often “wastefully chasing the outbreak, applying effort too late”.
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Microplastics found in all popular UK drinks, with hot beverages worst offenders
From your morning tea to a cold soft drink, UK beverages carry hidden microplastic loads, and hot drinks could be giving you an even bigger dose.
Study: Synthetic microplastics in hot and cold beverages from the UK market: Comprehensive assessment of human exposure via total beverage intake. Image Credit: SAG stock / Shutterstock
In a recent article published in the journal Science of the Total Environment, researchers assessed the levels of microplastics (MPs) that people are exposed to through their daily intake of fluids using survey data and laboratory analysis in the UK.
They detected MPs in all the beverages that people reported consuming and noted higher concentrations in hot drinks like tea, probably due to leaching from plastic packaging induced by heat, with average concentrations expressed in MPs per litre also reported for direct comparison.
Background
MPs, defined as synthetic particles between 1 μm and five mm in size, are persistent environmental contaminants found in marine, freshwater, terrestrial, and atmospheric environments. In practice, this study’s detection threshold was >10 μm due to μ-FTIR analytical limits. They can carry toxic chemicals, enter the food chain, and pose potential risks to human health.
Human exposure occurs through food, water, air, and consumer products, but drinking water studies dominate the research, showing variable MP concentrations across countries. Evidence also shows MPs in beverages like beer, tea, coffee, and soft drinks, with possible sources including the water used, packaging materials, manufacturing processes, and preparation methods.
While some studies report MPs in individual beverage types, no comprehensive assessment exists for a broad range of hot and cold beverages from one country. Furthermore, most exposure estimates consider only water intake, overlooking the role of other drinks in total fluid consumption.
Given that beverage choices vary socially and culturally, excluding them may underestimate exposure. Researchers addressed this gap by establishing baseline MPs data for widely consumed UK beverages, surveying daily beverage intake among UK adults, and combining this data to estimate MPs exposure from total fluid intake to provide a more realistic assessment essential for evaluating potential health risks.
About the Study
In this study, researchers analyzed MPs in 155 samples comprising 5 samples from 31 beverage types from popular UK brands, collected from supermarkets and coffee shops in 2024. Beverages included hot and iced coffee, hot and iced tea, juices, energy drinks, and soft drinks.
Samples were processed in a clean room under strict contamination controls. Cold drinks were filtered immediately, while hot drinks were cooled for 30 minutes before filtration. MPs were extracted by vacuum filtration through 0.45 μm silver membrane filters, followed by digestion of organic matter using hydrogen peroxide at 60 °C for 24 hours.
Analysis was performed using spectroscopy methods to identify polymer types and particle characteristics with a 70% or more spectral match. Shapes, sizes, and counts were determined via microscope imaging.
An online survey of 201 adults recorded daily beverage intake, which was combined with MPs concentration data (expressed in MPs/L in the primary results and in MPs/cup for product-specific discussion) from this study and previous UK water studies to estimate exposure in MPs/kg body weight/day. Quality control included blank samples and recovery tests. Statistical analyses assessed differences between beverage types.
Key Findings
MPs were detected in all 155 beverage samples analyzed. In MPs/L terms, hot coffee averaged 43 ± 14 MPs/L, iced coffee 37 ± 6 MPs/L, hot tea 60 ± 21 MPs/L, iced tea 31 ± 7 MPs/L, fruit juice 30 ± 11 MPs/L, energy drinks 25 ± 11 MPs/L, and soft drinks 17 ± 4 MPs/L.
For product-specific serving comparisons, hot coffee in disposable paper cups averaged 16 MPs/cup, much lower than some previous studies, as they excluded cellulose-based particles and focused only on synthetic polymers thicker than 10 μm. Coffee in glass cups had fewer MPs, while older coffee machines released more MPs, likely from material degradation. Iced coffee in cups made of polyethylene terephthalate (PET) averaged 11 MPs/cup, mostly PET, with possible contributions from ice. Ice used in iced coffee has previously been identified as a potential MP source. Hot coffee contained significantly more MPs than iced coffee.
Hot tea in paper cups averaged 22 MPs/cup, higher than tea in glass cups (14 MPs/cup). The most expensive tea bags had the highest MP counts, averaging 27 ± 3 MPs/cup. Iced tea in PET bottles had fewer MPs than hot tea, reinforcing heat’s role in MP release.
Fruit juice in PET bottles had higher MP levels (42 ± 4 MPs/L) than carton packs (23 ± 3 MPs/L). Energy drinks in plastic packaging contained more MPs (40 ± 7 MPs/L) than canned versions (18 ± 3 MPs/L). Soft drinks in plastic bottles averaged 17 ± 4 MPs/L, in line with international studies.
Particle sizes ranged mostly from 10–200 μm, with iced tea having the smallest particles and hot tea the largest. Across all beverages, fragments dominated (72–93%) over fibres. Polymer types matched packaging materials, with polypropylene (PP) the most abundant overall, followed by polystyrene (PS), polyethylene terephthalate (PET), and polyethylene (PE). Detection of polyamide (PA) and polylactic acid (PLA) in some tea and coffee sachets was linked to intentional inclusion for texture. This confirmed packaging as a major MP source, with additional contributions from production processes, air, and water, including atmospheric deposition and wear from plastic machinery parts.
Conclusions
In this study, researchers revealed widespread MP contamination across popular UK beverages, with higher levels in hot drinks, underscoring the role of temperature in accelerating MP release from packaging.
Polymer composition largely reflected packaging materials, but secondary sources, such as contaminated water, atmospheric fallout, and production equipment, also contribute. Estimated daily intakes from all beverages were 1.7 MPs/kg body weight/day for females and 1.6 MPs/kg body weight/day for males, exceeding UK drinking-water-only estimates, suggesting that water-based exposure assessments underestimate true intake.
Strengths include a large sample size across multiple brands, focus on synthetic polymers, and polymer-type identification. The inclusion of a local consumption survey allowed estimation of real-world exposure.
Limitations involve the use of regional consumption data rather than national statistics, potential market representation gaps, and a detection limit excluding MPs less than 10 μm. This size restriction may underestimate the total MP burden.
Overall, the findings provide robust evidence that beverage consumption contributes significantly to microplastic ingestion. The research team highlighted the need for more comprehensive monitoring, improved packaging materials, and public awareness, in line with the discussion in the paper.
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Brain’s energy control map offers blueprint for next-gen weight loss therapies
A deep dive into the brain’s command center for hunger shows how decoding its circuits could transform the future of weight loss treatments.
Brain integration of environmental cues in the regulation of energy balance and adiposity – Environmental factors (left) are integrated by the brain in the context of an individual’s genetic makeup (illustrated by highlighted SNPs) and epigenetic profile. In response, the brain regulates behavioral and physiological outputs, such as energy intake, energy expenditure, and fuel partitioning (middle), which all influence energy balance, ultimately shaping interindividual variation in adiposity (right).
In a recent review published in the journal Cell, a group of authors synthesized how the central nervous system (CNS) integrates neuroendocrine signals to govern energy homeostasis and translate these mechanisms into safe, effective anti-obesity pharmacotherapy.
Background
How did a survival system become a global health crisis? Since the 1980s, obesity rates have surged, now affecting around one billion people worldwide, with cardiovascular disease driving most obesity-related deaths. Genetics and environment interact: some bodies are primed to gain weight (“drifty gene” hypothesis), others resist, and modern food cues and stressors amplify the gap.
Obesity pathogenesis involves “push” (brain-driven hyperphagia) and “pull” (peripheral fuel sequestration) mechanisms. Meanwhile, brain circuits evolved to defend energy stores, not today’s ultra-processed diets. Understanding how the brain, gut, adipose tissue, and liver converse is key to developing safe, effective anti-obesity therapies. Further research is needed to map neural circuits and activity-dependent neuroplasticity that enable long-term, non-aversive weight loss.
Neuroendocrine Map of Energy Homeostasis
The brain arbitrates energy balance by blending slow adiposity signals with fast, meal-linked cues. Adipose tissue relays status through leptin, while the gastrointestinal (GI) tract releases hormones like glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), secretin, and ghrelin (the only orexigenic hormone in this list) from the stomach to stimulate appetite via agouti-related peptide (AgRP) neurons. These endocrine signals complement vagal and spinal afferents that sense gut distension and nutrients, giving the CNS rapid feedback.
Together, endocrine and neural inputs coordinate digestion, satiety, and metabolic homeostasis. The liver adds its voice, fibroblast growth factor 21 (FGF21), insulin-like growth factor 1 (IGF-1), and liver-expressed antimicrobial peptide 2 (LEAP2), while small metabolites and bile acids round out the message.
Hypothalamic Circuits: Setting the Energy Budget
The arcuate nucleus (ARC), adjacent to the median eminence (a circumventricular organ (CVO)), has privileged access to circulating hormones and metabolites. ARC neurons express receptors for leptin, ghrelin, and insulin and receive inputs from the paraventricular hypothalamus (PVH), ventromedial hypothalamus (VMH), and dorsomedial hypothalamus (DMH), and extrahypothalamic hubs such as the bed nucleus of the stria terminalis (BNST) and nucleus of the solitary tract (NTS).
Hunger-promoting AgRP neurons release γ-aminobutyric acid (GABA), neuropeptide Y (NPY), and AgRP to inhibit satiety circuits, while pro-opiomelanocortin (POMC) neurons release α-melanocyte-stimulating hormone (α-MSH) to activate melanocortin 4 receptor (MC4R) neurons and curb intake. Synaptic plasticity in these circuits (e.g., leptin-dependent reorganization of inputs) adapts to energy states. These ARC outputs project broadly, allowing hypothalamic networks to set appetite and expenditure.
Hindbrain & Vagal Control: Satiety Without Sickness
The dorsal vagal complex (DVC) integrates visceral signals to terminate meals. In the NTS, calcitonin receptor (CALCR) neurons, including a prolactin-releasing peptide (PRLH) subset, suppress feeding without aversion and can restrain AgRP-driven hunger via polysynaptic pathways.
By contrast, area postrema (AP) circuits can pair appetite suppression with malaise: growth differentiation factor 15 (GDF15) acts via glial cell line-derived neurotrophic factor (GDNF) family receptor alpha-like (GFRAL) neurons that activate parabrachial calcitonin gene-related peptide (CGRP) cells.
Region-specific glucagon-like peptide-1 receptor (GLP-1R) signaling matters: GLP-1R action in the AP drives aversion, whereas GLP-1R action in the NTS promotes satiety, suggesting why some drugs feel smoother than others.
Hormonal, metabolic, and neural inputs to brain circuits regulating energy homeostasis – (A) Simplified overview of peripheral signals arising from multiple organ systems, along with sensory cues from the external environment. These signals are integrated by the central nervous system to regulate energy intake and expenditure, maintaining stable adiposity over time. This regulation involves both long-term energy storage signals, such as leptin, and short-term signals related to immediate intake of energy, like gastrointestinal hormones and nutrients. (B) The arcuate nucleus of the hypothalamus harbors the melanocortin circuit, which is highly responsive to deviations in circulating hormones (e.g., those from the gastrointestinal tract) and the adipose tissue and metabolites. Central to this circuit are hunger-promoting AgRP neurons and satiety-promoting POMC neurons. These neuronal populations modulate energy balance via inhibitory and excitatory inputs to downstream MC4R-expressing neurons, respectively. (C) Many peripheral inputs influencing brain circuits that regulate energy balance originate in the gut. Enteroendocrine cells release hormones, like secretin, GLP-1, GIP, CCK, and others, into the circulation in response to various stimuli, such as the presence of luminal nutrients. Additionally, vagal afferents relay mechanical and chemical information—such as gut distension and nutrient content—from the gastrointestinal tract to the brain.
Motivation & Reward: Why Palatable Foods Win
Mesocorticolimbic pathways, ventral tegmental area (VTA) dopamine projections to the nucleus accumbens (NAc) and prefrontal cortex, assign incentive salience to food cues. The lateral hypothalamus (LH) interfaces with these reward circuits through melanin-concentrating hormone (MCH) and orexin neurons, which project to the VTA and NAc and bias seeking of palatable foods. Because homeostatic and hedonic systems interlock, effective therapies must dampen the drive to eat without flattening everyday motivation. Gut-to-brain signaling via the vagus can activate dopamine neurons after sugar sensing, helping explain why ultra-processed foods feel compelling even without strong taste cues.
From Circuits to Medicines: What Works Now
Earlier drugs worked mainly through monoamines (dopamine, norepinephrine, serotonin), as in phentermine–topiramate or bupropion–naltrexone, yielding about 8%-10% loss with cardiovascular, GI, and psychiatric trade-offs. Peptide engineering changed the game: reversible albumin binding extended incretin half-life, enabling GLP-1 therapies; liraglutide produced a 5.4% placebo-corrected loss at 56 weeks in people with obesity without diabetes.
Co-engaging glucose-dependent insulinotropic polypeptide receptor (GIPR) can blunt GLP-1R–linked aversion while preserving intake suppression, one plausible reason dual incretins achieve greater weight loss. Amylin receptor (AMYR) agonists, which act through CALCR–receptor activity-modifying protein (RAMP) complexes in the AP and ARC, also suppress intake and may do so with fewer aversive signals. Notably, the single-molecule GLP-1R/AMYR co-agonist amycretin drove 24% weight loss in a phase 1/2 trial.
Knowledge Gaps with Real-World Stakes
Key unknowns include which neuron populations sustain non-aversive satiety, how diet and stress reshape synapses in hypothalamic, hindbrain, and reward networks, and how to ‘rewire’ maladaptive circuits safely. Answering these questions would refine patient-specific therapy (choice of incretin backbone, amylin receptor add-ons), reduce discontinuation, and extend cardiometabolic benefits for families and health systems for many patients.
Conclusions
To summarize, the brain is the command center of energy homeostasis. By integrating endocrine signals from adipose tissue, the GI tract, the pancreas, and the liver with rapid neural input, central circuits, from ARC melanocortin pathways to DVC and mesocorticolimbic networks, set appetite, expenditure, and reward.
Peptide pharmacotherapies that target GLP-1R, GIPR, and amylin pathways already deliver meaningful weight loss. Future success will depend on mapping activity-dependent neuroplasticity and designing combinations that maximize satiety, minimize aversion, and protect long-term cardiometabolic health for people everywhere.
Journal reference:
- Johansen, V. B. I., Petersen, J., Lund, J., Mathiesen, C. V., Fenselau, H., & Clemmensen, C. (2025). Brain control of energy homeostasis: Implications for anti-obesity pharmacotherapy. Cell, 188(16), 4178–4212. DOI: 10.1016/j.cell.2025.06.010 https://www.cell.com/cell/fulltext/S0092-8674(25)00677-4
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Landmark study offers new insights into what protects against dengue
The specific components of the immune response in a human body that protect against a dengue virus (DENV) infection and the subsequent illness remain unclear. Scientists are still trying to understand how natural infection and vaccination protect people so that they can develop better vaccines.
Now, a novel study has revealed important insights into developing strong immunity against DENV, which is otherwise quite complex. Researchers from the US and Philippines have identified specific antibodies, known as envelope dimer epitope (EDE)-like antibodies, as the key for building broad, cross-serotype immunity following natural infection or vaccination.
The findings, published recently in Science Translational Medicine, represent a significant step forward in understanding dengue immunity and could lead to more effective therapeutics.
Disease burden and dengue vaccines
Dengue is a major global health challenge caused by any of four DENV serotypes (DENV1 to DENV4). It is the most common vector-borne viral disease, with half of the world’s population at risk, especially in Southeast Asia, Africa, and the Americas. According to one large study in 2013, the economic burden of dengue in Southeast Asia is higher than that of 17 other conditions, including Japanese encephalitis, upper respiratory infections, and hepatitis B.
And yet developing a universally effective vaccine has proven difficult thanks to the complex immune mechanisms involved. In DENV cases, the initial immunity after first infection (a.k.a. primary immunity) paradoxically increases the risk of severe disease rather than conferring protection when a person is infected a second time with a different serotype of the virus. This phenomenon, called antibody-dependent enhancement, occurs when non-neutralising antibodies bind to partially immature virus particles, facilitating their entry into immune cells and worsening the infection. All severe dengue cases requiring hospitalization result from such second infections.
Since vaccines mimic natural infections, the risk of antibody-dependent enhancement after the first dose is the main challenge for dengue vaccines, which is why they are usually recommended only for individuals with prior exposure to the virus and avoided in dengue-naïve people.
After exposure to at least two different DENV serotypes, a person develops true protection, known as “secondary immunity”, against future disease.
Currently, two primary dengue vaccines are licensed (in some countries): Dengvaxia and QDENGA. These shots are most effective for individuals who have already been exposed to dengue at least once before vaccination. Laboratory confirmation of a previous dengue infection is required for vaccination with Dengvaxia.
Outbreak in Cebu
DENV is an enveloped virus, meaning it has a protective outer layer. A key component of this layer is the envelope (E) protein, which is the primary target for the body’s immune response.
The E protein is arranged in pairs on the virus surface, creating complex three-dimensional structures known as quaternary epitopes. EDE is a critical quaternary epitope and an important target for vaccines and therapeutic antibodies.
In June 2017, Cebu province in the Philippines offered at least the first dose of a dengue vaccine to children aged 9-14 years. For the new study, the researchers recruited and followed a cohort of 2,996 such children. Of them, 1,782 received the first dose of the vaccine and the rest remained unvaccinated. The researchers collected baseline blood samples one month before the vaccination campaign and follow-up samples 17-28 months after the campaign.
There had been an unusually large dengue outbreak in Cebu between the baseline and follow-up sample collection, with most cases caused by DENV2 (61.7%) followed by DENV3 (30%). The researchers measured different kinds of antibodies in the samples: EDE-like antibodies (targetting envelope dimer epitopes); neutralising antibodies (which can block infection by mature, fully formed viruses); and binding antibodies (those that attached to parts of the E protein without necessarily blocking infection).
The study focused on the children who had had evidence of at least two prior DENV infections (those with “secondary immunity”) at the baseline. They followed up with the cohort up to October 31, 2022, to check how many with secondary immunity went on to develop dengue between the follow-up sample collection and the study closure date. All the samples were analysed in vaccinated and unvaccinated children in this subgroup in an attempt to reveal the true predictors of protection.
More protective against disease
The study’s findings illuminated the role of EDE-like antibodies in the protective response.
Specifically, the researchers found that EDE-like antibodies were highly prevalent in children with secondary DENV immunity, with 81.8% to 90.1% of participants having detectable levels. This was in stark contrast to individuals with only primary DENV immunity, where EDE-like antibodies were largely absent (detected in only 4% to 12% of cases). This suggests EDE-like antibodies are a hallmark of established immunity against dengue. The magnitude of EDE-like antibodies was also strongly and consistently correlated with broad neutralisation of all four mature DENV serotypes, indicating that these antibodies are crucial for widespread protection rather than just against a single serotype.
The study observed that both natural DENV infection — due to the large outbreak during the study period — and vaccination significantly boosted EDE-like antibodies as well as general DENV-binding and neutralising antibodies. This effect was evident even in children who already possessed strong secondary immunity.
Crucially, higher levels of EDE-like antibodies were consistently associated with lower odds of symptomatic dengue, dengue with warning signs, and dengue requiring hospitalisation. This protective effect was observed across multiple serotypes, demonstrating both serotype-specific and cross-reactive benefits. However, EDE-like antibodies had limited protective effects against viral replication. Thus, they were less protective against new infections but more protective against disease, especially severe disease.
Perhaps the most significant finding was that EDE-like antibodies didn’t just correlate with protection: they statistically explained a substantial portion of the protective effect seen with other mature virus-neutralising and E-binding antibodies. That is, when EDE-like antibodies were factored into statistical models, the protective effect of other antibodies was significantly diminished while EDE-like antibodies remained strongly associated with protection.
Specifically, EDE-like antibodies explained 42% to 65% of the protective effect attributed to mature virus-neutralising antibodies and 41% to 75% of the effect of general E protein-binding antibodies. This observation strongly suggested that EDE-like antibodies are a primary, underlying determinant of broad, cross-reactive immunity against dengue.
Limitations and the future
Although the study had some limitations, such as a relatively small number of dengue cases for assessing protection against all four serotypes and a limited panel of monoclonal antibodies used for characterisation, it nonetheless marked a significant advance in the fight against dengue.
The team provided a clearer understanding of the immune responses that truly protect against this debilitating disease. EDE-like antibodies also helped explain how neutralising and binding antibodies contributed to protection.
Further research will be essential to formally validate EDE-like antibodies as reliable indicators of protection for vaccine efficacy trials. If this is validated, researchers will be able to design vaccines that specifically elicit high levels of EDE-like antibodies and thus better protect against dengue.
Puneet Kumar is a clinician, Kumar Child Clinic, New Delhi. Vipin M. Vashishtha is director and paediatrician, Mangla Hospital and Research Center, Bijnor.
Published – August 12, 2025 05:30 am IST
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A Genetic Mutation Linked to ALS and Dementia Miswires Gene Expression
Newswise — It may be time to rethink certain genetic mutations associated with two devastating neurodegenerative disorders—amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—according to a new Nature Neuroscience study from researchers at Yale School of Medicine (YSM).
ALS is a devastating neurological disease marked by the progressive degeneration of nerve cells in the brain and spinal cord. In some cases, ALS can be accompanied by FTD, a type of dementia that causes damage to the temporal and frontal lobes of the brain, resulting in changes to behavior, personality, and speech.
While the cause for most ALS and FTD cases is still unknown, genetic mutations play a significant role, particularly in cases where there’s a family history of these disorders. The most common genetic mutation in European and North American populations with these conditions lies within the C9orf72 gene.
If we can identify these regulators, they could become potential targets for manipulating and reversing these abnormal events.
Junjie Guo, PhD Interestingly, unlike most genetic mutations that cause human diseases, the C9orf72 mutation is located within what is called an intron of the gene. Introns are typically considered “silent” regions within most genes in our DNA. While both introns and their counterparts known as exons are initially transcribed into RNA, introns are later removed during a process called splicing, leaving only the exons to form the mature messenger RNA (mRNA) transcripts that carry instructions to assemble proteins.
Therefore, introns are not expected to participate in producing proteins. But an apparent exception lies in C9orf72.
Within the first intron of this gene, a mutation causes a short DNA sequence to repeat itself hundreds of times. According to the typical understanding of introns, these repeats, when transcribed into RNA, should be removed by splicing and should not lead to protein production. But recent studies have shown that these repeats do in fact produce toxic repeat proteins that can accumulate in the brain and spinal cord, potentially contributing to neurodegeneration.
“These repeat proteins can interfere with a wide range of cell functions,” explains Suzhou Yang, a PhD student in Yale’s Interdepartmental Neuroscience Program and lead author of the study. “But it has been a mystery how an intronic sequence, which is usually cut out and degraded, can be translated into these toxic proteins.”
But now, Yang and Junjie Guo, PhD, associate professor of neuroscience at YSM and senior author of the study, have uncovered a crucial mechanism that helps solve this mystery. Their study, published on Aug. 11, has the potential to expand therapeutic possibilities for ALS and FTD, and provide insights into other diseases associated with similar mutations.
Aberrant splicing turns introns into exons
A major challenge in understanding the biology of the C9orf72 mutation has been the extremely low abundance of the mutant RNA molecules in patient cells—there’s just not a lot of it available to work with. To overcome this challenge, Yang and Guo developed a novel method to isolate and characterize these rare RNA molecules.
This allowed them to discover an important piece of the puzzle as to why the repeats were not removed through splicing—the intron in question actually becomes part of an exon.
Normally, the cell’s splicing machinery precisely removes introns from RNA and pieces back together the neighboring exons. But in this case, the presence of the repeat sequences somehow misdirects the splicing machinery, causing a portion of the intron, including the repeats, to be retained in the mature RNA.
“Part of the reason why it took us so long to find this is perhaps our static way of thinking about the genome and gene expression,” says Guo. “But once we saw the RNA sequence, this abnormal process immediately jumped out to us.”
They found that certain previously known splicing factors play a role in shaping the aberrant splicing patterns. Furthermore, collaborating with their colleagues from the iPSC-Neurocore in Yale’s Department of Neuroscience, they observed that different cell types carrying the same mutation, such as skin fibroblasts and motor neurons, exhibit different splicing outcomes.
Further research is still needed to fully understand how the repeat sequences cause C9orf72 aberrant splicing.
“It is most likely that there are additional cell-type-specific splicing regulators that determine the incorrect splice sites,” Guo explains. “If we can identify these regulators, they could become potential targets for manipulating and reversing these abnormal events.”
Expanding therapeutic possibilities for ALS and FTD
With approximately 10% of ALS cases caused by this C9orf72 mutation, Yang and Guo’s results indicate new possibilities for ALS and FTD treatment. Earlier work on therapeutic development has focused on eliminating C9orf72 repeat RNAs in order to reduce the production of toxic proteins and slow down neurodegeneration. A common drawback of current approaches, however, is that they struggle to distinguish between the harmful RNA with the repeats and the normal mRNA that encodes an important protein.
The new findings point to a novel approach that targets either the misdirected splicing or the resulting aberrant RNA. As proof of principle, the researchers designed molecules that selectively bind to the aberrant splice junction, a unique sequence only present in the repeat-containing RNA. Working with their collaborators at Mayo Clinic, the researchers found that these molecules effectively reduced the harmful repeat RNAs and their protein products.
“From the therapeutic perspective, we believe that this is a broadly applicable strategy of identifying unique sequences that could allow us to design therapeutic candidates to selectively target the disease-causing RNA,” Guo explains.
But there’s another major takeaway of the study.
“We must be cautious about categorizing mutations simply according to existing gene models,” says Guo. “Because it turns out, an intron does not always stay an intron.”
Other authors of this study include Denethi Wijegunawardana, Tanina Arab, Manasi Agrawal, Jeffrey Zhou, and João D. Pereira, from Yale School of Medicine, as well as Udit Sheth, Austin Veire, and Tania Gendron from Mayo Clinic.
The research reported in this news article was supported by the National Institutes of Health (awards DP2GM132930 and R35GM152208) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was also supported by the McKnight Foundation. Junjie Guo is a New York Stem Cell Foundation−Robertson Neuroscience Investigator.
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Popular AI Chatbots Are Spreading False Medical Info, Mount Sinai Researchers Say – MedCity News
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