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Category: genetics

Faulty protein cleanup gene tied to severe early-onset neurological disorders

Though protein clumps associated with Alzheimer’s and Parkinson’s were discovered more than a century ago, researchers remain largely unable to prevent them from forming or eliminate them from the brain. And though a variety of therapies have taken aim at tau tangles, beta-amyloid plaques and Lewy bodies, among other notorious aggregates, none have been very effective at stopping disease progression.

Rockefeller’s Hermann Steller and his team in the Strang Laboratory of Apoptosis and Cancer Biology have long been focused on understanding how the cell’s protein-degrading machines, called proteasomes, are regulated. His lab discovered that a transporter protein termed PI31 shuttles proteasomes over long distances from the nerve cell body to synapses. When this system fails, synapses become depleted of degradative capacity, and proteins that should have been eliminated accumulate. As a result, synaptic communication breaks down, protein clumps form and neuronal health deteriorates.

Now a new study in Nature Communications, led by researchers from University College London and contributed to by Steller’s lab, has identified mutations in PSMF1, the gene that produces PI31, that cause the protein to malfunction. Moreover, the scientists demonstrated that these mutations cause a spectrum of severe, very early-onset neurological disorders.

Making CAR T Cells Safer

Research from CCR scientists points toward a strategy for making chimeric antigen receptor (CAR) T-cell therapy, the cell-based immunotherapy that has revolutionized the treatment of some blood cancers, safer and more effective for treating solid tumors.

The study, led by Grégoire Altan-Bonnet, Ph.D., Deputy Chief of the Laboratory of Integrative Cancer Immunology, Naomi Taylor, M.D., Ph.D., Senior Investigator in the Pediatric Oncology Branch, and Paul François, Ph.D., at the University of Montréal, shows how adding certain receptors to CAR T cells can prevent the cells from attacking healthy tissue while simultaneously enhancing their activity against cancer cells. The findings appeared April 10, 2025, in Cell.

CAR T-cell therapy reprograms patients’ immune cells to be effective cancer killers using genetically engineered chimeric antigen receptors (CARs) that are added to their T cells. CARs are designed to recognize molecules on the surface of cancer cells called antigens, which can usually be found on some healthy cells, too. This leads to manageable side effects for patients with blood cancer, but when CAR T cells designed to target solid tumors attack healthy tissue, the effects can be severe.

Genomes from Oceania offer new clues to human evolution

A new Yale-led study provides one of the most detailed and comprehensive analyses to date of genetic variation in human populations in Oceania, filling a major gap in representation in genomics research. Despite harboring remarkable diversity, populations in this vast region in the South Pacific historically have been overlooked in global human genetic studies, which have often focused largely on people of European descent, researchers say. The study is published in the journal Science.

“The drastic underrepresentation of Oceanians limits our understanding of human evolution and could exacerbate health inequalities as genomic research is used to develop novel medical treatments,” said lead author Serena Tucci, assistant professor of anthropology in Yale’s Faculty of Arts and Sciences and principal investigator of the Yale Human Evolutionary Genomics Laboratory. “To fill that gap, my research team embarked on a large-scale project to expand what is known about human genetic variation, including genetic variants inherited from extinct hominins.”

The work shows how the genes that ancient humans acquired after mating with extinct hominins continue to shape the biology, health and survival of our species today.

CRISPR enzyme precisely detects and shreds DNA in cancer mutations once considered ‘undruggable’

In 2020, Jennifer Doudna won the Nobel Prize in chemistry for her work on the CRISPR-Cas9 gene-editing technology that allows scientists to precisely modify DNA by cutting it at specific locations. Six years later, a new study in Nature by a team led by Doudna has uncovered a powerful new approach to selectively kill cancer cells using a CRISPR enzyme called Cas12a2.

Once the enzyme detects cancer-specific genetic signatures, it begins to shred chromatin—a mixture of DNA and proteins that forms chromosomes—within the targeted cell.

Many cancers are driven by mutations in tumor suppressor proteins such as TP53, which is altered in nearly half of all cases. Yet these mutations have remained difficult to treat because they lack binding pockets for traditional drugs to latch onto. As a result, many cancer-causing mutations have long been considered undruggable.

Silver nanoparticles pave the way for precise DNA cutting and joining

DNA is composed of long chains that act as the blueprint for living organisms. In genetic engineering, scientists cut DNA at specific sites and join the resulting fragments to other DNA sequences, enabling applications such as advanced crop breeding, treatment of genetic diseases, and the generation of animal models for drug discovery.

Assembling short DNA fragments requires overhanging sequences, known as sticky ends, to facilitate efficient binding. However, generating sticky ends requires precise cutting at targeted sites, which remains challenging with current technologies.

A Japanese research group has developed a silver nanoparticle-based technology to precisely cut and join DNA at targeted sites, achieving two to five times higher DNA assembly efficiency than conventional restriction enzyme methods. These findings were published in the journal Nucleic Acids Research.

Researchers trigger sleep’s restorative effect in parts of the awake brain

Scientists from the University of Wisconsin-Madison have successfully replicated some of the restorative effects of deep sleep in awake mice by artificially inducing slow-wave brain activity. Using optogenetics to control specific neurons, researchers triggered localized cortical activity that mimics the NREM sleep phase responsible for synaptic homeostasis and the reorganization of neural connections. This targeted stimulation significantly reduced signs of fatigue and improved memory retention and cognitive performance in the mice following prolonged wakefulness. While the researchers caution that this technique is not a substitute for natural sleep, the findings suggest that localized neural stimulation can effectively preserve brain function during extended periods of wakefulness. Future research aims to explore whether similar cognitive benefits can be achieved in humans through non-invasive methods, such as transcranial electrical stimulation.

NIH-funded study in animals offers new details about how the brain resets during sleep.

By inducing specific patterns of activity in small portions of the brain in awake mice, researchers supported by the National Institutes of Health (NIH) have triggered a recalibration of neural connections that normally only occurs during sleep. This new approach offset the effects of sleep deprivation in memory tasks and revealed features of sleep that are key to its restorative effect.

“What we’re essentially doing is forcing sleep in a local region of the brain. While that part is solidifying memories and restoring learning capacity, other parts stay aware/vigilant and connected to environment,” said corresponding author Chiara Cirelli, M.D., Ph.D., a professor of psychiatry at the University of Wisconsin-Madison. “Dolphins do something similar, sleeping with only one brain hemisphere at a time.”

Frontiers: Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21

Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.

Down syndrome (DS) is a relatively high-incidence pathology (∼1 in every 800–1,000 live births; see Antonarakis et al., 2020; Hughes-McCormack et al., 2020) caused by triplication of Hsa21. Increased expression of Hsa21 genes (and genes on other chromosomes) impairs development and functions of various organs, including the brain (Bull, 2020). While some disorders may not be present in all individuals with DS, intellectual disability (ID) is the invariable hallmark of DS (Zigman, 2013; Ballard et al., 2016; Lott and Head, 2019). ID scores range from moderately (IQ of 50–70) to severely (IQ of 20–35; Bull, 2020) affected; even in its milder form, intellectual performance may compromise the ability to live independently. ID is already detectable in children with DS, especially regarding language, memory, and adaptive behavior, and is exacerbated with age (Godfrey and Lee, 2020).

Plasticity as a therapeutic target for improving cognition and behavior in Down syndrome

Early intervention and environmental optimization have been central to management of Down syndrome (DS) and much of current treatment is still focused in strategies that involve early education plans. This approach has provided significant improvements for Down syndrome but it is not providing a full success. The discovery of an increasing number of genes and molecular pathways linked to intellectual disability and involving a range of synaptic and plasticity-related mechanisms has open new treatment opportunities that focus on targeted treatments boosting neural plasticity. We here discuss some of these approaches, focusing on the effects of environmental enrichment and on the discovery of pharmacological therapies showing beneficial effects even in some clinical trials in adult individuals with Down syndrome. Targeting plasticity impairments in DS is thus a promising strategy to promote cellular mechanisms involved in learning and memory within key cognitive brain region and could lead to improved connectivity.

Keywords: EGCG; Environ-mimetic drugs; Environmental enrichments; Epigenetics; Neuronal plasticity.

© 2020 Elsevier B.V. All rights reserved.

Cholesterol-craving cancers need lipid enzymes to use metabolites for growth, study shows

While many American adults are trying to reduce cholesterol levels, certain cancerous tumors have a relentless appetite for the metabolite. Some tumor cells use as much cholesterol as they can access to accelerate their growth beyond the capabilities of normal cells.

Turning tumors’ cholesterol cravings into weakness Scientists at Sanford Burnham Prebys Medical Discovery Institute and their collaborators at the University of Illinois Chicago have published findings in Science Advances regarding a potential method for turning the tables on these tumors by subverting their cholesterol cravings. The researchers revealed new insights into enzymes that help move cholesterol around cells. Without the help of these enzymes, a cholesterol traffic jam occurs, blocking the cancer cell’s ability to fuel tumor growth.

Cancer cells with a mutation in the tumor-suppressing TP53 gene are known to produce extra cholesterol. This may make them more vulnerable to starvation if scientists can put a stop to the steady supply of the lipid.

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