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Category: genetics – Page 2

A genetic breakthrough links early-onset diabetes to brain disorders

Paediatric teams are now facing babies whose diabetes appears in the first weeks of life, then rapidly reveals deep problems in brain growth and function. A new genetic finding sheds light on how a single molecular fault can disrupt both blood sugar control and early brain development.

Neonatal diabetes is diagnosed in the first six months of life, often within days or weeks after birth. Unlike the more common type 1 diabetes, which usually shows up in children and teenagers, neonatal diabetes is almost always genetic.

Doctors typically notice poor feeding, weight loss, dehydration and extremely high blood sugar. In many cases, the root cause is a mutation that stops the pancreas from making enough insulin. That alone makes neonatal diabetes a medical emergency.

Two harmful gene variants can restore function when combined, study reveals

Sometimes, in genetics, two wrongs do make a right. A research team has recently shown that two harmful genetic variants, when occurring together in a gene, can restore function—proving a decades-old hypothesis originally proposed by Nobel laureate Francis Crick.

Their study, to be published in the Proceedings of the National Academy of Sciences, not only experimentally validated this theory but also introduced a powerful artificial intelligence (AI)-driven approach to genetic interpretation led by George Mason University researchers.

The project began when Aimée Dudley, a geneticist at the Pacific Northwest Research Institute (PNRI), approached George Mason University Chief AI Officer Amarda Shehu after following her lab’s work on frontier AI models for predicting the functional impact of genetic variation. That conversation sparked a collaboration that married PNRI’s experimental expertise with George Mason’s computational innovation to discover some surprising ways variant combinations can shape human health.

Motor protein discovery in fruit flies may unlock neurodegenerative secrets

Scientists have long known that inherited neurodegenerative disorders, including Alzheimer’s, Parkinson’s or motor neuron disease, can be traced back to genetic mutations. However, how they cause the diseases remains unanswered.

In today’s issue of the journal Current Biology Professor Andreas Prokop revealed that so-called “motor proteins” can provide key answers in this quest.

The research by the Prokop group focuses on nerve fibers, also called axons. Axons are the delicate biological cables that send messages between the brain and body to control our movements and behavior. Intriguingly, axons need to survive and stay functional for our entire lifetime.

UNM Researchers Discover New Master Regulator of Tau, a Protein Implicated in Many Neurodegenerative Diseases

In a surprising discovery, University of New Mexico researchers have found that OTULIN – an enzyme that helps regulate the immune system – also drives the formation of tau, a protein implicated in many neurodegenerative diseases, as well as brain inflammation and aging.

In a study published in the journal Genomic Psychiatry, the researchers reported that when they deactivated OTULIN, either by administering a custom-designed small molecule or knocking out the gene that codes for it, it halted the production of tau and removed it from neurons. The study was conducted on two different types of cells, some derived from a patient who had died from late-onset sporadic Alzheimer’s disease, and the rest from a line of human neuroblastoma cells that are frequently used in neuroscience research.

The discovery opens the door to potential treatments for Alzheimer’s and other neurodegenerative diseases, said Karthikeyan Tangavelou, PhD, a senior scientist in the lab of Kiran Bhaskar, PhD, professor in the Department of Molecular Genetics & Microbiology in the UNM School of Medicine.

Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation

Significance.

Cellular rejuvenation through transcriptional reprogramming has emerged as exciting approach to counter aging. However, to date, only a few of rejuvenating transcription factor (TF) perturbations have been identified. In this work, we developed a discovery platform to systematically identify single TF perturbations that drive cellular and tissue rejuvenation. Using a classical model of human fibroblast aging, we identified more than a dozen candidate TF perturbations and validated four of them (E2F3, EZH2, STAT3, ZFX) through cellular/molecular phenotyping. At the tissue level, we demonstrate that overexpression of EZH2 alone is sufficient to rejuvenate the liver in aged mice, significantly reducing fibrosis and steatosis, and improving glucose tolerance. Our work expanded the list of candidate rejuvenating TFs for future translation. Abstract.

Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging—increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species. Sign up for PNAS alerts.

Get alerts for new articles, or get an alert when an article is cited. Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging and bring cells back to a healthy state. In both cell and animal aging models, there has been significant recent progress in rejuvenation research. Systemic factors identified in young blood through models such as heterochronic parabiosis (in which the circulatory systems of a young and aged animal are joined) rejuvenate various peripheral tissues and cognitive function in the brain (1–4). Partial reprogramming at the cellular level with the Yamanaka factors (four stem cell transcription factors) reverses cellular and tissue-level aging markers and can extend lifespan in old mice (5–8). These discoveries support the notion that transcriptional reprogramming is a powerful approach to improving the health of cells and tissues, and one day could be used as an approach for human therapeutics. However, to date, only a couple of rejuvenating transcription factor (TF) perturbations have been identified (9, 10) and most of them require the overexpression of TFs. We hypothesized that there are multiple other TF perturbations which could reset cells and tissues back to a healthier or younger state—rejuvenating them. Identifying complementary rejuvenating strategies is important as it will increase the chance of successful future translation. We developed a high-throughput platform, the Transcriptional Rejuvenation Discovery Platform (TRDP), which combines computational analysis of TF binding motifs and target predictions (Materials and Methods), global gene expression data of old and young cell states, and experimental genetic perturbations to identify which TF can restore overall gene expression and cell phenotypes to a younger, healthier state. We developed TRDP to be applicable to any cell type, and in both aging and disease settings, with the only requirements being baseline comparison of gene expression data comparing the older/diseased state to the younger/healthier state and the ability to perform genetic perturbations. To model aging in vitro as a validation of our approach, we used the canonical aging model of passaged fibroblasts (11, 12). We tested 400 TF perturbations via our screen and validated reversal of key cellular aging hallmarks in late passage human fibroblasts for four top TFs: E2F3, EZH2, STAT3, and ZFX. Moreover, EZH2 overexpression in vivo rejuvenated livers in aged mice—reversing aging-associated global gene expression profiles, significantly reducing steatosis and fibrosis, and improving glucose tolerance. These findings point to a conserved set of molecular requirements for cellular and tissue rejuvenation.

Inflammation fuels one of the most aggressive forms of cancer

Unlike other epithelial cancers, small cell lung cancer (SCLC) shares features with neuronal cells, including lack of caspase-8 expression, a protein involved in programmed, non-inflammatory cell-death (apoptosis), a mechanism that is essential to eliminate faulty or mutated cells and to maintain health.

To better mimic the features of human SCLC, the team generated and characterized a novel genetically engineered mouse model lacking caspase-8. Using this new model, the team observed that when this protein is missing, an unusual chain reaction sets off.

“The absence of caspase-8 leads to a type of inflammatory cell death called necroptosis that creates a hostile, inflamed environment even before tumors fully form” explains the senior author. “We were also intrigued to find that pre-tumoral necroptosis can in fact promote cancer by conditioning the immune system,” the author continues.

The inflammation creates an environment where the body’s anti-cancer immune response is suppressed, preventing immune cells from attacking threats like cancer cells. This, in turn, can promote tumor metastasis. Surprisingly, the researchers observed that this inflammation also pushes the cancer cells to behave more like immature neuron-like cells, a state that makes them better at spreading and that is associated with relapse.

While it remains unknown whether similar pre-tumoral inflammation also occurs in human patients, this work identifies a mechanism contributing to the aggressiveness and patient relapse in SCLC that could be exploited as a way to improve the efficiency of future therapies and early-stage diagnostic methods. ScienceMission sciencenewshighlights.

Small cell lung cancer (SCLC) is one of the most aggressive forms of lung cancer, with a five-year survival rate of only five percent. Despite this poor prognosis, SCLC is initially highly responsive to chemotherapy. However, patients typically relapse and experience very rapid disease progression. Current research into the biological mechanisms behind SCLC remains essential in order to prolong treatment responses, overcome relapse and, ultimately, improve long-term patient outcomes.

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Beta-Hydroxy-Butyrate: A Key Player In Longevity?

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The Intelligence Revolution: Coupling AI and the Human Brain | Ed Boyden | Big Think

The Intelligence Revolution: Coupling AI and the Human Brain.
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Edward Boyden is a Hertz Foundation Fellow and recipient of the prestigious Hertz Foundation Grant for graduate study in the applications of the physical, biological and engineering sciences. A professor of Biological Engineering and Brain and Cognitive Sciences at MIT, Edward Boyden explains how humanity is only at its infancy in merging with machines. His work is leading him towards the development of a “brain co-processor”, a device that interacts intimately with the brain to upload and download information to and from it, augmenting human capabilities in memory storage, decision making, and cognition. The first step, however, is understanding the brain on a much deeper level. With the support of the Fannie and John Hertz Foundation, Ed Boyden pursued a PhD in neurosciences from Stanford University.

EDWARD BOYDEN:

Edward Boyden is a professor of Biological Engineering and Brain and Cognitive Sciences at the MIT Media Lab and the McGovern Institute for Brain Research at MIT. He leads the Media Lab’s Synthetic Neurobiology group, which develops tools for analyzing and repairing complex biological systems, such as the brain, and applies them systematically both to reveal ground truth principles of biological function and to repair these systems.

These technologies, often created in interdisciplinary collaborations, include expansion microscopy (which enables complex biological systems to be imaged with nanoscale precision) optogenetic tools (which enable the activation and silencing of neural activity with light,) and optical, nanofabricated, and robotic interfaces (which enable recording and control of neural dynamics).

Boyden has launched an award-winning series of classes at MIT, which teach principles of neuroengineering, starting with the basic principles of how to control and observe neural functions, and culminating with strategies for launching companies in the nascent neurotechnology space. He also co-directs the MIT Center for Neurobiological Engineering, which aims to develop new tools to accelerate neuroscience progress.

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New Mega-Analysis Reveals Why Memory Declines With Age

A landmark international study that pooled brain scans and memory tests from thousands of adults has shed new light on how structural brain changes are tied to memory decline as people age.

The findings — based on more than 10,000 MRI scans and over 13,000 memory assessments from 3,700 cognitively healthy adults across 13 studies — show that the connection between shrinking brain tissue and declining memory is nonlinear, stronger in older adults, and not solely driven by known Alzheimer’s-associated genes like APOE ε4. This suggests that brain aging is more complex than previously thought, and that memory vulnerability reflects broad structural changes across multiple regions, not just isolated pathology.

Published in Nature Communications, the study, “Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change,” found that structural brain change associated with memory decline is widespread, rather than confined to a single region. While the hippocampus showed the strongest association between volume loss and declining memory performance, many other cortical and subcortical regions also demonstrated significant relationships. This suggests that cognitive decline in aging reflects a distributed macrostructural brain vulnerability, rather than deterioration in a few specific brain regions. The pattern across regions formed a gradient, with the hippocampus at the high end and progressively smaller but still meaningful effects across large portions of the brain.

https://www.nature.com/articles/s41467-025-66354-y

Genetic risk for Alzheimer’s and widespread brain shrinkage linked to greater memory loss — even in otherwise healthy adults.

Three-parent babies: Mitochondrial replacement therapies

The mitochondria are membrane-bound intracellular organelles present in almost all eukaryotic cells (). They generate energy through oxidative phosphorylation, and are responsible for 90% of cellular ATP (). In mammals, the mitochondria are present in all cells, except the enucleated red blood cells, being more present in tissues that need energy metabolism, with several units of the organelle. They have a round or oval shape and are about 0.5 to 1 µm in diameter, and up to 7 µm in length (). Together with the cell nucleus, they are the only cell organelle having their own genome, an extremely compact molecule, with 16.500 base pairs and 37 genes: 13 messenger RNAs, 22 RNAs, and 2 ribosomal RNAs. The D-loop is the only non-coding region in mtDNA, since introns and intergenic regions are non-existent or restricted to a few nucleotides ().

In addition to the production of reactive oxygen species due to the release of free electrons generated from the respiratory chain, mitochondria have few repair systems and therefore are subject to genetic mutations, causing diseases that affect approximately 1 in 5,000 people (). Mitochondrial diseases can affect organs that depend on energy metabolism, such as skeletal muscle, cardiac, central nervous system, endocrine, retina and liver (; ), giving rise to several incurable diseases, such as: deafness, diabetes mellitus, myopathies, glaucoma and others (). These metabolic disorders, lead to inefficient oxidative phosphorylation, impairing cell energy production (). They are difficult to diagnose and most of the time untreated, affecting adults and children ().

Mitochondria are inherited only from the female gamete; therefore, the mitochondrial DNA is of exclusive maternal inheritance (). The genetic mutations present in this material can be avoided using mitochondrial substitution techniques (), where the nuclear genome is withdrawn from an oocyte, which carries mitochondrial mutations, and is implanted in a normal enucleated donor ().

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