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The most abundant element on Earth — sodium — may hold the key for scientists to develop opioids or other drugs with far fewer side effects.
In a study published Wednesday by Nature, scientists from USC, Washington University in St. Louis and Stanford University demonstrated that by chemically linking fentanyl to the sodium pockets that exist within nerve cell receptors, they could block the drug’s harmful side effects and still reduce pain.
Further study is needed but the results hold promise — not just for drug development but for addressing the nation’s crisis of addiction and overdose. Nearly 70,000 Americans died in 2020 of an opioid overdose — most of them from the synthetic opioid, fentanyl, according to the National Institute on Drug Abuse. In 1990s, the Food and Drug Administration approved the use of fentanyl to ease severe pain in cancer patients but it has since made its way into the streets, worsening the national crisis of opioid abuse.
“In its current form, fentanyl is like a weapon of mass destruction,” said Vsevolod Katritch, a computational scientist at the Bridge Institute at USC Michelson Center for Convergent Bioscience and a corresponding author of the study. “Our new collaborative work suggests that we could redesign the drug in such a way that we convert this frequent overdose killer to a much more benign but still effective analgesic.”
Drugs of all kinds are designed to target certain receptors on nerve cells known as GCPRs, or G-coupled protein receptors, which act as signal transmitters. These receptors are like switches that mediate a drug’s intended effect on the brain and body, but also the unintended side effects. In the case of fentanyl, the most potent painkiller of all opioids, patients may suffer addiction and may die from respiratory arrest.
Katritch noted that he and his fellow scientists Ray Stevens and Vadim Cherezov at the Bridge Institute and the USC Dornsife College of Letters, Arts and Sciences have been looking at the potential of the sodium mechanism since they first identified it within adenosine and opioid receptors about a decade ago.
Katritch and his collaborators said that although further study is needed to prove that their less harmful version of fentanyl will work in humans, the results have opened a new door for scientists to potentially improve the safety of painkillers.
“We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that too often lead to death,” said corresponding author Susruta Majumdar of Washington University in St. Louis. “Our research is still in its early stages, but we’re excited about its potential for leading to safer pain-relieving drugs.”
Beyond opioid receptors, noted Katritch, this work opens a new molecular design concept for dozens of other GPCRs where such functional conversion in existing drugs would be desirable.
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Materials provided by University of Southern California. Original written by Emily Gersema. Note: Content may be edited for style and length.

In the pandemic’s first year, death rates linked to alcohol and drugs climbed among seniors as lockdowns and isolation spread.Deaths due to substance abuse, particularly of alcohol and opioids, rose sharply among older Americans in 2020, the first year of the coronavirus pandemic, as lockdowns disrupted routines and isolation and fear spread, federal health researchers reported on Wednesday.Alcohol and opioid deaths remained far less common among older people than among those middled-aged and younger, and rates had been rising in all groups for years. But the pronounced uptick — another data point in the long list of pandemic miseries — surprised government researchers.Deaths from opioids increased among Americans aged 65 and older by 53 percent in 2020 over the previous year, the National Center for Health Statistics found. Alcohol-related deaths, which had already been rising for a decade in this age group, rose by 18 percent.“The rate of alcohol deaths in older people is much lower than for younger adults, but the change caught our eye,” said Ellen Kramarow, a health statistician at the center and the lead author of the report, which analyzed death certificate data.Overdose deaths from synthetic opioids account for fewer than 1 percent of deaths in people over 65, Dr. Kramarow noted. “But the shape of the curve jumped out at us,” she said.Physiological changes that occur with aging leave older adults more vulnerable to the ill effects of alcohol and drugs, as metabolism and excretion of substances slow down, increasing the risk of toxicity. Smaller amounts have bigger effects, researchers have found.Alcohol and opioids can interact poorly with prescription medications that many older adults take for common conditions like hypertension, diabetes and mood disorders. Misuse can lead to falls and injuries, exacerbate underlying medical conditions and worsen declines in cognition.Fentanyl Overdoses: What to KnowCard 1 of 5Devastating losses.

What drives tumor growth? Is it a few rogue cells imposing their will upon healthy tissue, or diseased tissue bringing out the worst in otherwise peaceable cells? Or is it a back-and-forth, a dialogue between the two? According to a new study, it may be the latter, at least when it comes to the progression of one common skin cancer.
Researchers found that a single mutated gene in an otherwise healthy stem cell can kick off an increasingly deviant feedback loop of miscommunication between the cancerous stem cell and its surrounding tissue, fueling the development of a malignant tumor. The findings suggest that many of the mutations in cancer may simply be setting in stone a path already forged by the tumor stem cell’s aberrant dialogue with its surroundings. If these results, published in Nature, prove broadly applicable, the findings could pave the way for novel approaches to treating a range of cancers.
“It’s not just that cancer molds the microenvironment, or that the environment affects the tumor,” says first author Shaopeng Yuan, a graduate student in the laboratory of Elaine Fuchs at The Rockefeller University. “Our study shows that there is crosstalk between the microenvironment and the stem cells in tumors. They communicate with each other and create a loop of tumor-promoting factors.”
Spotlight on squamous cell carcinoma
At the heart of almost every tumor is a small subset of cancer stem cells. Resistant to chemotherapy and immunotherapy, these malignant seeds are the cells responsible for keeping the tumor alive and are key players in the process that turns benign growths into metastatic disease. And behind many cancer stem cells, including those of skin, pancreatic, lung, and colorectal cancers, is a RAS gene that, when mutated, allows tissue stem cells to ignore normal environmental signals and deviate from their natural course, promoting out-of-control tissue growth.
To better understand the finer points of that interaction, Yuan and colleagues turned their attention to squamous cell carcinoma, a skin cancer linked to RAS mutations. The team started off by inducing mutant HRAS (the member of the RAS family most common in skin cancers) in individual skin stem cells, and monitoring how the cancerous stem cells interacted with the surrounding tissue. “Over time, the dialogue between the cancer stem cell and its microenvironment became more and more aberrant,” Fuchs says. “As we deciphered the dialogue, we realized that the miscommunication between the stem cell and its microenvironment resulted in the activation of much the same pathway that is active in the corresponding human cancers that harbor a high mutational burden.”
This observation raised an intriguing possibility. Perhaps many cancer mutations do not set the course of a disease so much as lock it in place, affirming a malignant progression already determined by aberrant crosstalk between a cancer stem cell and its microenvironment.

A new paper sheds light on the nature of atomic nuclei.
Everything in the universe, from the largest galaxies down to individual atoms, is governed by four fundamental forces, which together describe how particles interact with each other and make up the world as we know it. These include the electromagnetic force, gravity and the weak and strong nuclear forces.
After a recent study out of the U.S. Department of Energy’s (DOE) Argonne National Laboratory and the University of North Carolina at Chapel Hill, researchers are one step closer to understanding the strong nuclear force, one of the most mysterious of the forces.
Their work builds on foundational theories of atomic structures that originated with Argonne physicist and Nobel Prize winner Maria Goeppert Mayer in the early 1960s. She helped develop a mathematical model for the structure of nuclei. Her model explained why certain numbers of protons and neutrons in the nucleus of an atom cause it to be extremely stable — a phenomenon that had baffled scientists for some time.
The research team previously conducted similar experiments to study the strong nuclear force by examining how the structure of a nucleus can change when it is produced in an excited state through a nuclear reaction. These and other experiments done elsewhere led them to investigate nickel-64, which has 64 neutrons and protons. This nucleus is the heaviest stable nickel nucleus, with 28 protons and 36 neutrons. This nickel isotope has properties that allow its structure to change when it is excited to higher energy states.
For their experiment, the team used the Argonne Tandem Linac Accelerator System, a DOE Office of Science user facility, to accelerate a sample of Ni-64 nuclei toward a target of lead. The lead atoms were able to excite the Ni-64 nuclei through the electromagnetic forces resulting from the repulsion between the protons in lead and the protons in nickel.

Scientists at the Francis Crick Institute, in collaboration with Artios, have identified how an enzyme involved in DNA repair (POLQ), becomes vital to the survival of certain cancers, if the cancer cells lose the ability to use a more common method of DNA repair.
The work uncovers an unappreciated role for POLQ in responding to DNA replication stress, providing the scientific underpinnings for a Phase I clinical trial evaluating the effects of blocking this enzyme in cancer patients.
Polymerase theta (POLQ) is a DNA repair enzyme that is selectively upregulated and highly active in many types of cancers. Research has suggested that blocking POLQ can prevent some cancer cells from repairing their DNA, ultimately leading to cancer cell death.
“There are several properties of POLQ that make it an exciting target to explore as a potential Achilles Heel for treating different cancers,” explained Simon Boulton, senior author, principal group leader at the Crick and scientific co-founder and VP of scientific strategy at Artios. “POLQ is mainly expressed in cancer cells but is virtually absent in healthy cells. Many cancers become reliant on POLQ to repair DNA damage, a key response important for tumour survival.”
When DNA is replicated, the two strands that make up the double helix are separated, and each strand is used as a template to synthesize a new double helix. However, this process can go wrong, and lead to errors such as the formation of gaps in DNA. There are several types of DNA repair mechanisms that are designed to repair these errors so that replication can continue normally.
In their research, published online in Molecular Cell today (30 November), the scientists studied how DNA gaps are repaired in human cancer cells using advanced imaging tools that monitor DNA replication in real time. They found that POLQ provides a vital repair mechanism in cancer cells unable to repair DNA gaps using a common method called homologous recombination.

A new study links a gene concentrated in the brain’s cleanup cells, known as microglia, to the inflammation that has increasingly emerged as a key mechanism contributing to Alzheimer’s disease. The findings may offer a new potential target for therapies for the intractable condition.
The gene, known as inositol polyphosphate-5-phosphatase D (INPP5D), is the subject of a collaborative study conducted by researchers from the Icahn School of Medicine at Mount Sinai and the Grossman School of Medicine at NYU Langone Health that appears in the November 30 issue of Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
Microglia are immune cells in the brain that act as scavengers to remove dying cells and amyloid plaques that are associated with the dementia of Alzheimer’s disease. Human genetics studies initially linked INPP5D to the risk for Alzheimer’s disease. Other studies revealed elevated levels of INPP5D in the postmortem brain tissue of Alzheimer’s disease patients, but the specific role(s) that the gene plays in both early or late disease and the mechanism contributing to these altered functions remains unknown.
Because INPP5D in the brain is concentrated in microglia, co-senior author Michelle E. Ehrlich, M.D., Professor of Neurology, Pediatrics, and Genetics and Genomic Sciences at Icahn Mount Sinai, used mice genetically engineered to “knock down” (turn off) the mouse INPP5D gene in their microglia at the onset of pathology. This process allowed them to better see the specific impact of the missing gene on brain tissue. They then measured plaque buildup and microglial behavior approximately three months later. Since INPP5D was known to be elevated in the brains of Alzheimer’s patients, the scientists expected that the mice with that gene inactivated would be protected from the amyloid plaques that are hallmarks of Alzheimer’s disease pathology.
“When I looked through the microscope, I was quite surprised to see that the mice lacking INPP5D in their microglia had more plaques that mice with normal microglia,” said Emilie Castranio, PhD, a postdoctoral fellow in Dr. Ehrlich’s lab and co-first author on the new paper. “Microglia frequently sit on the edges of the plaques but when INPP5D was knocked down, the plaques were completely covered with them.”
“We are encountering unexpected results more and more with modulation of inflammation genes in Alzheimer’s,” said Dr. Ehrlich. “At this point in our understanding, we still do not know which of these genes to target for therapeutic intervention in humans, or whether to turn them up or turn them off depending on disease stage. Because these experiments are not possible in living humans, we rely on mouse models to show us the way. We also use these mice to help us predict whether a particular gene is more related to disease onset or disease progression, with the caveat that mouse and human microglia differ in important ways. Despite these differences, the plaque-associated gene signature we identified overlaps with human Alzheimer’s disease gene networks.”
When it became clear that the INPP5D knockdown moved microglia around the brain in unexpected ways, Dr. Ehrlich recognized that detailed spatial and quantitative gene expression information was required. Spatial transcriptomics is a molecular profiling method that allows scientists to measure all the gene expression in a tissue sample and map where the expression is occurring. Drs. Ehrlich and Castranio turned to Shane Liddelow, PhD, Assistant Professor of Neuroscience, Physiology, and Ophthalmology at NYU Langone, and co-senior author of the new study, who is a world leader in this approach.
The spatial transcriptomics findings emphasized the range of gene expression changes that microglia can display. Microglia near amyloid plaques are known to express genes designated as plaque-induced genes (PIGs). The INPP5D knockdown mice replicated the increases in PIGs that had been described in previous research, but the high quality of both the technical aspects and analysis of the spatial transcriptomics allowed for the identification of additional PIGs. The newly identified PIG with the greatest increase in expression in these mice was CST7, a gene encoding the protein cystatin F that is known to be impacted in Alzheimer’s and associated with prion diseases, a family of rare, progressive neurodegenerative disorders that affect both humans and animals. These findings suggest that both INPP5D and cystatin F should be considered as targets for development of novel interventions aimed at mitigating inflammation in the Alzheimer’s brain.
Funding for the study was provided by National Institutes of Health grants P30AG066515, U01AG046170, RF1AG058469, RF1AG059319, R01AG061894, P30AG066514, U01AG046170, RF1AG057440, U01AG046170, and RF1AG057440. Additional funding was provided by the Blas Frangione Foundation, the Neurodegenerative Diseases Consortium from MD Anderson Cancer Center, Alzheimer’s Research UK, the Gifford Family Neuroimmune Consortium as part of the Cure Alzheimer’s Fund, the Alzheimer’s Association, and NYU Langone’s Alzheimer’s Disease Resource Center. Further funding was provided by Paul Slavik.
Liddelow maintains a financial interest in AstronauTx Ltd., a company investigating possible treatment targets for Alzheimer’s disease. The terms and conditions are being managed in accordance with the policies of NYU Langone.
In addition to Drs. Ehrlich and Castranio, other Icahn Mount Sinai investigators in the study were Jean-Vianney Haure-Mirande, PhD; Angie Ramirez, BS; Bin Zhang, PhD; Minghui Wang, PhD, and Sam Gandy, MD, PhD. Other study authors include study co-lead author Philip Hasel, PhD, and Rachel Kim, BA, at NYU Langone, and Charles Glabe, PhD, from the University of California, Irvine.

A Michigan State University researcher is part of an international team that found an existing drug may help decrease side effects of cisplatin, a widely used cancer treatment that was discovered at MSU in 1965.
Since its discovery, cisplatin has become the gold standard against which all cancer treatments are measured. Currently, cisplatin is used to treat testicular, ovarian, bladder, lung, stomach and head and neck cancers. While cisplatin has proven to be an effective chemotherapy drug to treat cancer, the side effects of the treatment can be debilitating and may result in treatment cessation. Examples of such side effects include peripheral neuropathy, which causes severe pain in hands and feet, and kidney toxicity, which can lead to kidney failure in 35% of patients who take cisplatin. Currently, no drugs are available that reduce these side effects.
Patients taking cisplatin undergo weekly blood tests to monitor kidney function and look for kidney damage caused by the drug to determine whether they can safely withstand another round of treatment. If a patient experiences kidney toxicity, current options include pausing treatment or reducing the dosage of the chemotherapy. Some patients choose to discontinue treatment because the painful neuropathy in their extremities is too intense.
Now, there may be a solution to help patients beat cancer and reduce the severity of their treatment’s side effects. MSU researcher Geoffroy Laumet, along with his team and an interdisciplinary group of scientists from the University of Lille, the University of Strasbourg and the Pasteur Institute of Lille in France and the University of Coimbra in Portugal, has found that istradefylline, a drug already approved by the FDA and used to treat Parkinson’s disease, can reduce the side effects of cisplatin while preserving its cancer-fighting strength.
Laumet is an assistant professor in the College of Natural Science who specializes in cisplatin-induced neuropathic pain. While the researchers in France and Portugal showed that istradefylline reduces kidney toxicity, together with Laumet, the international team demonstrated that istradefylline also can alleviate peripheral neuropathy and improve tumor control.
“The exact interaction between istradefylline and cisplatin remains to be determined but we do know that tumor cells and cells that are stressed by the toxicity of cisplatin will release a lot of adenosines,” Laumet said. “Istradefylline blocks the effects of adenosine.”
While istradefylline has been proven to be safe in humans, the current experiments showing its efficacy in combating the side effects of cisplatin have only been conducted on animal models. The next step is for the team to collaborate with researchers that specialize in human clinical trials.
“The preclinical research results have been promising,” said Laumet. “In the future with istradefylline, the hope is that patients would be able to keep taking cisplatin without side effects or losing the drug’s effectiveness.”
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Materials provided by Michigan State University. Original written by Emilie Lorditch. Note: Content may be edited for style and length.

A collaboration between Ghent University in Belgium and Cleveland Clinic’s Florida Research & Innovation Center (FRIC) found a new way genetics influences the body’s antiviral response by studying a life-threatening disease caused by a common virus: herpes simplex virus 1 (HSV-1).
The researchers analyzed genetic data from a patient with immunodeficiency and hospitalized at nine months old with herpes encephalitis, a rare but life-threatening brain inflammation after HSV-1 infection. They identified novel mutations in the gene GTF3A, and found that these mutations impair the innate immune response.
The findings, published in Science Immunology, hold potential as a genetic marker doctors could use to gauge a child’s risk of herpes encephalitis, although such mutations are generally very rare in the population.
Many people are infected in childhood with the HSV-1 virus but the vast majority don’t suffer from encephalitis. The most common symptom of HSV-1 is oral cold sores, but many people show no signs at all. HSV-1 is more threatening to children and adults who are immunodeficient, whose immune system cannot control the virus well.
“Genetic and mechanistic analyses of uncommon viral diseases like herpes encephalitis are quite rare. In fact, the causes underlying severe herpes encephalitis are often unknown,” says Michaela Gack, Ph.D., FRIC’s scientific director. “This information provides us with invaluable insight into the fundamental molecular processes that govern our immune response and opens up opportunities for future research on severe disease outcomes.”
The Ghent research team led by Filomeen Haerynck, M.D., Ph.D., reached out to Dr. Gack’s team after finding the mutations in the gene. Dr. Gack’s lab studies interactions between the human immune system and viruses on a molecular level.
The GTF3A mutations shape how cells respond to viral activity through the genetic makeup of a protein called TFIIIA. TFIIIA plays a role in helping a human enzyme produce certain types of RNA that can determine specific functions inside cells. Some RNAs can elicit an anti-herpes viral immune response.
Dr. Gack’s team tested cells that have the mutations, and found that because of defects in certain immunostimulatory RNAs, the cells were more susceptible to HSV-1 infection and lost the ability to control the HSV-1 virus.
The affected gene is part of the body’s defense system that produces interferons to combat viruses. Interferons are crucial to the human immune response and for suppressing virus infection and spread.
This new genetic pathway could be helpful in understanding the immune response to other viruses, like Epstein-Barr virus, a common virus linked to mononucleosis and associated with certain types of cancer and multiple sclerosis.
“Understanding the molecular processes underlying antiviral responses is key to treating or possibly preventing severe viral infections that change patients’ and families’ lives,” Dr. Gack said. “Our findings on critical immune defense proteins may translate into new therapies in the future.”
The study was funded through U.S. National Institutes of Health grants AI165502 and AI087846, and the Flanders Institute for Biotechnology (VIB) Grand Challenges program. The award from VIB, an entrepreneurial non-profit research institute, is to the Ghent University.
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Materials provided by Cleveland Clinic. Note: Content may be edited for style and length.

New research out of VCU Massey Cancer Center points to the inactivation of a previously unidentified gene as a likely culprit in the development of pancreatic cancer. Recently published in Cell Reports, the findings could alter the scientific understanding of this deadly disease and inform the establishment of novel treatments.
The findings hold implications for the targeted treatment of pancreatic ductal adenocarcinoma (PDAC), which accounts for the vast majority of all pancreatic tumors and is the fourth-leading cause of cancer-related deaths worldwide. Most patients are diagnosed at an advanced stage when the disease is already inoperable and there are no effective therapies.
Extensive research has demonstrated that mutations in the KRAS gene play an enormous role in the formation and growth of pancreatic cancer. Approximately 85-90% of all pancreatic tumors have a KRAS mutation.
“Given its high incidence at very early stages of the disease, mutational activation of KRAS has been hypothesized as the key genetic driver for pancreatic cancer,” said study corresponding author Azeddine Atfi, Ph.D., leader of the Cancer Biology research program who holds the Mary Anderson Harrison Distinguished Professorship in Cancer Research at Massey.
However, there is a substantial fraction — around 10-15% — of PDAC tumors that harbors an offset of the conventional KRAS mutation, characterized as “wild-type KRAS.” This suggests that in many cases alternate genetic drivers are responsible for the development of cancer.
Atfi’s new research suggests that the inactivation of NF1 — a gene known as Neurofibromin-1 that holds natural tumor-suppressing functions — could be instrumental in the onset of pancreatic cancer, either in tandem with KRAS, bolstering its cancer-driving properties, or even before any mutations occur in the KRAS gene, in partnership with TP53, the most inactivated tumor suppressor gene in human malignancies.
Atfi and his collaborators determined that removing NF1 in mice without KRAS mutations directly resulted in the early developmental stages of pancreatic tumors, but also enhanced the cancer-driving function of KRAS in mice with mutations.
“We found that genetic inactivation of NF1 dramatically accelerates the formation and progression of KRAS-mediated pancreatic cancer,” said Atfi, who is also a professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine. “This study raises the provocative possibility that targeting NF1 in mutant KRAS-bearing pancreatic tumors might create vulnerabilities that could be exploited for therapeutic advantage.”
Additionally, the researchers observed a strong association between NF1 and p53, another protein widely known for its tumor-suppressing functions. They found that the simultaneous inactivation of both NF1 and p53 directly correlated to pancreatic cancer growth, regardless of any mutations in the KRAS gene.
“The notion that the combined inactivation of NF1 and p53 represents an alternative initiating event in PDAC provides an unprecedented platform for the future identification of novel targeted treatment options for pancreatic cancer,” Atfi said.
Atfi collaborated on this research with Creighton Friend and Eric Hurwitz of the VCU School of Medicine; Parash Parajuli, Ph.D., Gopalakrishnan Ramakrishnan, Pura Singh, and Keli Xu, Ph.D., of the University of Mississippi Medical Center; Celine Prunier of the Sorbonne Université; and Mohammed Razzaque, M.B.B.S., Ph.D., of the Lake Erie College of Osteopathic Medicine.
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Materials provided by Virginia Commonwealth University. Original written by Blake Belden. Note: Content may be edited for style and length.

In our cells, the language of DNA is written, making each of us unique. A tandem repeat occurs in DNA when a pattern of one or more nucleotides — the basic structural unit of DNA coded in the base of chemicals cytosine (C), adenine (A), guanine (G) and thymine (T) — is repeated multiple times in tandem. An example might be: CAG CAG CAG, in which the pattern CAG is repeated three times.
Now, using state-of-the-art whole-genome sequencing and machine learning techniques, the UNC School of Medicine lab of Jin Szatkiewicz, PhD, associate professor of genetics, and colleagues conducted one of the first and the largest investigations of tandem repeats in schizophrenia, elucidating their contribution to the development of this devastating disease.
Published in the journal Molecular Psychiatry, the research shows that individuals with schizophrenia had a significantly higher rate of rare tandem repeats in their genomes — 7% more than individuals without schizophrenia. And they observed that the tandem repeats were not randomly located throughout the genome; they were primarily found in genes crucial to brain function and known to be important in schizophrenia, according to previous studies.
“We think this discovery opens doors for future functional studies on the precise biological mechanism of such variants,” said Szatkiewicz, who is also adjunct assistant professor of psychiatry. “Understanding the biological cause of schizophrenia will enable future development of diagnostic tests, effective pharmaceuticals, and personalized treatments.”
Tandem repeats usually don’t have negative health implications. However, based on the location of tandem repeats in the genome and how long they are, they can contribute to disease. For example, Huntington’s disease is caused by a tandem repeat in the HTT gene that has been abnormally expanded. Onset of the disease will happen once the sequence of cytosine-adenine-guanine (CAG) repeats more than 36 times on the HTT gene. The longer repeat expansions lead to abnormal protein products with an extended track of glutamine that is toxic to brain cells. These repeats are inherited and tend to grow longer and longer in successive generations with increasing disease severity or decreasing age of onset.
In their current study, Szatkiewicz and her team looked at the entire genomes of 2,100 individuals to find tandem repeats that looked abnormally long and were unique or rare. Because all participants provided access to their medical records, the team was able to compare these long and rare repeat DNA sequence samples from people who had schizophrenia versus samples from people in the study who didn’t. This allowed the researchers to determine which of these tandem repeats may be involved with the development of schizophrenia.
Using gene network analysis, the authors of this study demonstrated that genes with rare tandem repeats found in schizophrenia primarily impact synaptic and neuronal signaling functions. In addition, these genes are highly evolutionarily conserved, indicating important biological functions and therefore the significant impact that tandem repeats might exert.
The UNC School of Medicine researchers then collaborated with scientists from The Hospital for Sick Children in Toronto to see if this increased level of rare tandem variants would also be found in another independently collected group of samples. The Szatkiewicz findings were replicated in the Canadian investigation, indicating that this newly discovered link between tandem repeats and schizophrenia is quite strong.
“We think this is an important study,” said co-senior author Ryan Yuen, PhD, senior scientist at the Hospital for Sick Children and assistant professor of molecular genetics at the University of Toronto. “We’re confident our work sheds significant light on the role of tandem repeat DNA mutations play in the development of schizophrenia.”
Other authors of the paper are Jia Wen, Brett Trost, Worrawat Engchuan, Matthew Halvorsen, Linda M. Pallotto, Aleksandra Mitina, NaEshia Ancalade, Martilias Farrell, Ian Backstrom, Keyi Guo, Giovanna Pellecchia, Bhooma Thiruvahindrapuram, Paola Giusti-Rodriguez, Jonathan David Rosen, Yun Li, Hyejung Won, Patrik K. E. Magnusson, Ulf Gyllensten, Anne S. Bassett, Christina M. Hultman, and Patrick F. Sullivan.
This research was primarily funded through grants from the National Institute of Mental Health and the SciLifeLab National Project.