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Many neurodegenerative disorders such as Parkinson’s disease (PD) result from the combined effects of mutations in several genes (i.e., polygenic). Although previous studies have identified a few genes that are responsible for familial or sporadic cases of PD, we are still far from knowing the entire spectrum of genes that contribute to this complex disorder. Researchers at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and Baylor College of Medicine have recently developed an integrated functional genomics approach that led to the discovery of 50 genes that have been shown for the first time to modify PD pathology in a disease animal model. The study was published in Human Molecular Genetics.
The study was led by Dr. Juan Botas, professor at Baylor College and investigator at the Duncan NRI. The highlight of the study is a new multidisciplinary high-throughput approach the team developed to identify and functionally validate dozens of PD-causing and neuroprotective genes.
Usually, it takes several years to identify and functionally validate the role of a gene in a genetic disorder, and this is a particularly onerous task for a polygenic disease like PD. By integrating several computational and in vivo biological approaches within a single screening strategy, the team was able to identify and validate many PD gene candidates in a fairly short time.
Since 2005, Genome-Wide Association Studies (GWAS) have been used to analyze the genomes of large numbers of individuals to identify genomic variants that are statistically associated with increased risk for a complex genetic disorder. While this method reveals genetic loci/gene variants that may be potentially associated with a particular disease, further in-depth in vitro in cultured cells and/or in vivo studies in animal models are necessary to demonstrate the biological involvement of those variants in the pathogenesis of that disease, which are labor-intensive and time-consuming processes. In recent years, a new approach known as transcriptome-wide association study (TWAS) has been developed to predict genetic risk for complex diseases. Combining TWAS and GWAS with a machine learning algorithm gave them insights into the potential function of these variants. Nevertheless, genes identified by both methods need further experimental validation.
To speed up the gene validation process, the lead author of this study, graduate student, Jiayang Li, and others developed a multi-step approach that combined several computational and in vivo validation methods.
“First, we nominated 160 potential PD candidate genes via GWAS and TWAS, which were further analyzed using other state-of-the art computational tools and led to 80 high-confidence PD genes” Li said. “Second, we established a link between these candidates and PD-associated pathology by assessing if the expression patterns of these candidates were altered in brain and blood transcriptome of PD patients. Finally, to gauge functional relationships between these candidates and to assess which biological pathways they are involved in, we performed several in silico and in vivo analyses that finally resulted in 50 PD risk genes and 14 potentially neuroprotective genes.”
“Our success in identifying so many new variants and the remarkable congruence in the results we obtained at each step of this screen supports this is as a powerful method to identify and validate new PD candidate genes,” Dr. Botas said. “Moreover, as long as genomic information is readily available, this approach can be applied broadly to a wide range of complex genetic disorders and so, we anticipate this study to have a wide impact on disease areas much beyond PD.”
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Materials provided by Texas Children’s Hospital. Original written by Rajalaxmi Natarajan. Note: Content may be edited for style and length.

pinocerebellar ataxias are a group of neurodegenerative diseases characterized by the degeneration of Purkinje cells, a major class of neurons in the cerebellum. The resulting cerebellar dysfunction leads patients to experience a loss of motor coordination and control.
One subtype of the disease, spinocerebellar ataxia type 14 (SCA14), was found to be caused by mutations in protein kinase C-gamma (PKCγ), an enzyme that regulates other proteins in Purkinje cells. But exactly how these mutations alter the enzyme’s function to ultimately drive neurodegeneration remained unknown.
In a new study, published September 27, 2022 in Science Signaling, researchers at University of California San Diego School of Medicine found that SCA14-associated mutations disrupt the autoinhibition and degradation of PKCγ, leading to elevated levels of enzyme activity. This sustained “leaky” activity alters the Purkinje cell phosphoproteome to drive cerebellar pathology.
“Our findings reveal important mechanisms underlying spinocerebellar ataxia and position PKCγ as a promising therapeutic target for this neurodegenerative disease,” said senior author Alexandra C. Newton, PhD, Distinguished Professor of Pharmacology at UC San Diego School of Medicine.
To understand how the SCA14-associated mutations affect the enzyme’s function, researchers first measured activity levels of different PKCγ variants in cultured cells. Compared to more common PKCγ variants, those with SCA14 mutations in the protein’s C1A and C1B domains showed significantly enhanced enzymatic activity, which further experiments confirmed was due to conformational changes that impair the enzyme’s autoinhibition and degradation.
Autoinhibition is an on-site regulatory mechanism in which certain domains within a molecule’s structure act to repress its own function.
Researchers then found the enhanced PKCγ activity led to a cascade of downstream changes to the phosphorylation state of the cellular environment, particularly dysregulating signaling pathways involved in axon development and cytoskeletal structure.
The extent of disrupted PKCγ autoinhibition correlated with disease severity, and mutations that induced a particularly high level of PKCγ activity were also associated with an earlier age of disease onset.
PKCγ is itself regulated by intracellular calcium, and many other types of spinocerebellar ataxia are driven by mutations that affect calcium homeostasis. Thus, the authors suggest that targeting PKCγ may correct this broader signaling pathway and prove effective in treating multiple forms of the disease.
“This raises exciting possibilities for therapeutically targeting PKCγ not only in SCA14 but also in many other subtypes of spinocerebellar ataxia,” Newton said.
Co-authors of the study include: Caila A. Pilo, Timothy R. Baffi, Alexandr P. Kornev, Maya T. Kunkel, Mario Malfavon, Leigh-Ana Rossitto, David J. Gonzalez and Susan S. Taylor at UC San Diego; Dong-Hui Chen, Daniel X. Chen and Wendy H. Raskind at University of Washington; Liang-Chin Huang and Natarajan Kannan at University of Georgia; and Cheryl Longman and George Gorrie at Queen Elizabeth University Hospital.
The study was funded, in part, by the National Institutes of Health (grants R35GM122523, R01NS069719 and R35GM139656), the Zionic Ataxia Fund and the National Ataxia Foundation.
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Materials provided by University of California – San Diego. Original written by Nicole Mlynaryk. Note: Content may be edited for style and length.

Pennsylvania has one of the highest rates of opioid overdose in the nation, and, according to Penn State researchers, one’s chances of surviving that overdose can depend on where the person lives.
Using data from the Pennsylvania Overdose Information Network from the years 2018-20 and American Community Survey data from 2015-19, Penn State geography researchers looked at the prevalence of overdoses in the state and found the availability of the anti-overdose therapeutic naloxone to be a key factor in overdose survival. The findings were reported in the Journal of Drug and Alcohol Dependence.
Data showed individuals who received at least one dose of naloxone were nine times as likely to survive an overdose. Naloxone was administered in about 75% of the survival cases and just 29% of fatal overdose cases.
Yet, the availability of the drug at the time of overdose ranged between 41%-47% in the lowest counties such as nearby Clinton and Huntingdon Counties to 92% in Philadelphia County, the highest. In broad strokes, lesser populated counties had less access to the life-saving treatment, with exceptions for Centre and Mercer Counties, which fared better than similarly populated counties.
“One of the main goals of this research is to inform public health practitioners and policymakers who have the capacity to do something about the distribution of naloxone, which is clearly effective,” said Louisa Holmes, assistant professor of geography at Penn State, member of Penn State Social Science Research Institute’s Consortium on Substance Use and Addiction (CSUA) and lead author of the study. “It gives leaders a target for combating the opioid epidemic by saving lives.”
Data showed 82% of Pennsylvania adults survived opioid overdoses. In 2020, there were 4,314 opioid related deaths in the state, a 16% increase over 2019, according to the Pennsylvania Department of Health.

For the very first time, a study led by Julian Chen and his group in Arizona State University’s School of Molecular Sciences and the Biodesign Institute’s Center for the Mechanism of Evolution, has discovered an unprecedented pathway producing telomerase RNA from a protein-coding messenger RNA (mRNA).
The central dogma of molecular biology specifies the order in which genetic information is transferred from DNA to make proteins. Messenger RNA molecules carry the genetic information from the DNA in the nucleus of the cell to the cytoplasm where the proteins are made. Messenger RNA acts as the messenger to build proteins.
“Actually, there are many RNAs (ribonucleic acids) that are not used to make proteins,” explained Chen. “About 70 percent of the human genome is used to make noncoding RNAs that don’t code for protein sequences but have other uses.”
Telomerase RNA is one of the noncoding RNAs that assembles along with telomerase proteins to form the enzyme telomerase. Telomerase is crucial for cellular immortality in cancer and stem cells. In this study, Chen’s group shows that a fungal telomerase RNA is processed from a protein-coding mRNA, instead of being synthesized independently.
“Our finding from this paper is paradigm-shifting. Most RNA molecules are synthesized independently and here we uncovered a dual function mRNA that can be used to produce a protein or to make a noncoding telomerase RNA, which is really unique,” said Chen. “We will need to do a lot more research to understand the underlying mechanism of such an unusual RNA biogenesis pathway.”
Basic research on the metabolism and regulation of mRNA has led to important medical applications. For example, several COVID-19 vaccines use messenger RNA as a means to produce viral spike proteins. In these vaccines, the mRNA molecules are eventually degraded and then absorbed by our bodies.

Everyone breathes in Mycobacterium avium complex (MAC) bacteria from time to time, but most people don’t get sick. These bacteria, cousins of the deadly Mycobacterium tuberculosis, tend to live out their harmless little lives in food, soil, water, or dust.
Then there’s the rare person who gets very, very sick.
MAC is an “opportunistic” pathogen, explains Cecilia Lindestam Arlehamn, Ph.D., Research Assistant Professor at La Jolla Institute for Immunology (LJI). Some people do have risk factors — such as cystic fibrosis and structural lung diseases, for example — that make them likely to develop symptoms after MAC exposure. The problem is that no one knows exactly why these factors make such a difference.
Now Lindestam Arlehamn’s laboratory has uncovered an immune cell defect tied to the risk of developing MAC disease. As her team reports in Frontiers in Immunology, people who show MAC infection symptoms have fewer specialized Th1* (Th1 “star”) cells, which robs them of the ability to mount an effective immune response to the bacteria.
“We think these people have this cellular defect going into MAC exposure,” explains Lindestam Arlehamn, who worked closely on the study with collaborators at the University of Washington.
This research may be a step toward uncovering biomarkers to predict risk of progressive lung disease and responses to treatment in MAC disease patients.

Scientists at Scripps Research, IAVI, the Ragon Institute and Moderna, Inc., have come together to make critical advances in developing an effective vaccine against human immunodeficiency virus (HIV).
The findings were published on September 29, 2022, in Immunity in two individual papers. The research describes the first steps in a vaccine approach that aims to prompt the creation of broadly neutralizing antibodies (bnAbs) — antibodies that are broad enough to fight and protect against many different variants of a virus. By identifying the most promising bnAbs and the human genes needed to make them — as well as designing protein and mRNA vaccine candidates to begin bnAb creation and verifying the vaccine candidates — the team is paving the way to create an effective HIV vaccine.
“Our two studies describe a collaborative effort to genetically and structurally understand bnAbs, and ultimately ‘reverse engineer’ vaccines to elicit these bnAbs,” says senior author William Schief, PhD, a Scripps Research professor and executive director of vaccine design at IAVI’s Neutralizing Antibody Center at Scripps Research. “HIV has remained one of the most difficult viruses to protect against because of its natural ability to quickly mutate and evade capture from the immune system. Working closely together across scientific disciplines and institutions, our team’s findings mark a crucial step forward in overcoming these historic hurdles and creating an effective HIV vaccine.”
Building Backwards
Researchers have long studied how a small percentage of infected individuals with HIV are able to make bnAbs. Even when bnAbs do develop during infection in these cases, they arise too late to help block the virus. However, researchers have demonstrated that bnAbs can protect against the virus if they are present before a person gets infected with HIV. This observation has led scientists to try to develop vaccines that induce bnAbs in healthy individuals, but designing such vaccines has proved difficult.
The new work at Scripps Research, IAVI and Ragon aims to break the logjam by carefully choosing the bnAbs to elicit, and then designing custom vaccines that coax the immune system to produce the target bnAbs in a stepwise manner. The team focused on bnAbs that bind to the apex of the HIV spike protein (analogous to the spike protein of SARS-CoV-2). These apex bnAbs employ extremely long loops (called HCDR3 loops) to pierce the spike protein like a spear. By binding to the apex of the HIV spike, the bnAbs prevent HIV from infecting human cells.

Adjusting to a new sleep schedule at the start of the school year can lead to disturbed rest, daytime fatigue and changes in mood and focus for teens.
Although they need eight to 10 hours of sleep per night to maintain physical health, emotional well-being and school performance, according to the National Sleep Foundation and the American Academy of Sleep Medicine, most adolescents get less than eight, especially on school nights.
Newly published research from RUSH in the journal SLEEP sheds light on how adolescents can get more shut-eye.
“There are a lot of changes a teen goes through,” said Stephanie J. Crowley, PhD, associate professor of psychiatry and behavioral sciences and the director of the Pediatric Chronobiology and Sleep Research Program at RUSH. “One specifically is a change to sleep biology that happens during puberty.”
“The brain systems that control sleep change in such a way that it’s easier for an adolescent to stay awake later into the evening. One of these systems — the 24-hour circadian clock — shifts later in time,” Crowley said.
So there are two competing forces: one to go to bed earlier for the school schedule and the other a biological change that happens naturally to a teen’s body.

A research finding in mice that the drug gabapentin improved rehab compliance after spinal cord injury led scientists to a related, unexpected discovery: Injured mice that didn’t receive gabapentin and declined to exercise by themselves were willing to hop on the treadmill when presented with a group rehab option.
Researchers observed that in mice with spinal cord injury (SCI), those treated with gabapentin routinely participated in voluntary post-injury treadmill training. Mice that received a placebo were less engaged in voluntary rehab, and participation declined as they neared the chronic phase of post-injury disease.
Differences in the generation of new neurons and anxiety-like symptoms suggested gabapentin was protecting mental well-being in animals with SCI, leading researchers to consider a way to boost untreated animals’ drive to aid in their own recovery — by enabling group participation. Instead of having mice train alone on treadmills in lanes with structural dividers, scientists took the dividers away.
“The results were astonishing,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine. “We found that a social motivator was sufficient to rescue rehab participation in mice without the drug, and though it was modest, this promoted some degree of recovery as well.
“Given these results, and that mice and humans both require social interaction, we might start thinking about rehab strategies, and consider whether group intervention may be physically and emotionally beneficial for individuals with spinal cord injury.”
The study was published recently in the journal Frontiers in Molecular Neuroscience.

Mandatory mask wearing saw more than 90% of deaf people struggle to communicate during the pandemic, University of Essex research has revealed.
It also discovered that 76% missed vital information and 59% felt disconnected from society due to the face coverings.
This is because masks restrict the ability to read lips and judge expressions.
It also emerged that over-55s who became deaf later in life found communication using masks more challenging.
And profoundly deaf people and signers experienced more disconnection from society and negative effects on their wellbeing.
Dr Eva Gutierrez-Sigut, from the Department of Psychology, led a team of deaf and hearing researchers who made sure that the survey was accessible in different sign languages.

A nationwide U.S. study of more than 893,000 adults provides solid evidence confirming that mRNA booster immunizations extend protection against moderate and severe COVID for four to five months. These findings, published in The BMJ, provide a more complete understanding of the effectiveness and durability of third and fourth doses of the mRNA vaccines, informing policymakers and providing individuals with confirmation of the importance and value of boosters.
Vaccine effectiveness provided by boosters waned less against severe disease than against moderate disease in all age groups according to the new study which was conducted by the Centers for Disease Control and Prevention’s (CDC) VISION Network.
“While there have been recommendations for booster shots for a while, until now we haven’t had strong evidence of their effectiveness and how long that effectiveness lasts,” said study co-author Brian Dixon, PhD, of the Regenstrief Institute and Indiana University Richard M. Fairbanks School of Public Health. “In our new study, we looked at tens of thousands of patients in multiple states, seen over a year and a half. Our analysis provides compelling evidence, both of the effectiveness of boosting to increase immunity, and that this immunity begins to wane after four or five months, indicating additional booster doses are necessary.
“The recommendations to get boosted that were issued by the CDC months ago, were, in fact, the right recommendations,” said Dr. Dixon. “Booster doses are necessary to maintain a high level of immunity to severe COVID.”
The bivalent booster, available since early September 2022, targets both historic strains of the SARS-CoV-2 virus and the Omicron variants (BA.4 and BA.5) currently circulating in the U.S. and globally.
Building on their initial, preliminary analysis, published in CDC’s Morbidity and Mortality Weekly Report, in the new study, the VISION Network scientists analyzed data from patients seen at 261 hospitals, 272 emergency departments and 119 urgent care clinics in 10 states across the U.S. from January 17, 2021 to July 12, 2022. The data covered periods of Omicron dominance (including subvariants BA.4 and BA.5), as well as the previous periods of Delta and pre-Delta dominance. The new study is published in The BMJ.