Publisher Health

Some regions of the human genome where the DNA can fold into unusual three-dimensional structures called G-quadruplexes (G4s) show signs that they are preserved by natural selection. When G4s are located in the regulatory sequences that control how genes are expressed or in other functional, but non-protein coding, regions of the genome, they are maintained by selection, are more common, and their unusual structures are more stable, according to a new study. Conversely, the structures are less common, less stable, and evolve neutrally outside of these regions, including within the protein-coding regions of genes themselves.
Together, these lines of evidence suggest that G4 elements should be added to the list of functional elements of the genome along with genes, regulatory sequences, and non-protein coding RNAs, among others. A paper describing the study, by a team of researchers led by Penn State scientists, appears June 29, 2021 in the journal Genome Research.
“There have been only a handful of studies that provided experimental evidence for individual G4 elements playing functional roles,” said Wilfried Guiblet, first author of the paper, a graduate student at Penn State at the time of research, and now a postdoctoral scholar at the National Cancer Institute. “Our study is the first to look at G4s across the genome to see if they show the characteristics of functional elements as a general rule.”
As much as 1% of the genome can fold into G4s, rather than the typical double helix (in comparison, protein-coding genes occupy approximately 1.5% of the genome). G4s are one of several non-canonical shapes into which DNA can fold, collectively known as “non-B DNA.” The G4 structure forms in DNA sequences rich in the nucleotide guanine, the “G” in the ACGT alphabet of the genome. G4s have been implicated in several key cellular processes and have been suggested to play a role in several human diseases, including neurological disorders and cancer.
To better understand the function of G4s at a genome-wide scale, the research team looked at their distribution across the genome, their thermostability, and whether or not they showed signs of being under the influence of natural selection, all in relation to other functional elements of the genome. They confirmed that, as a rule, G4s are more common in regions of the genome known to have important cellular functions and that the G4s in these regions are more stable than elsewhere in the genome.
“The three-dimensional structure of G4s can form transiently and how stable their structure is depends on their underlying DNA sequence and other factors,” said Guilbet. “We found that, usually, G4s located within functional regions of the genome tend to be more stable. In other words, it’s more likely that the DNA is folded into a G4 at any given time and thus, more likely that the G4 is there for a functional reason.”
Functional regions of the genome are generally maintained by a type of natural selection called purifying selection. Mutations in these regions could disrupt their function and be harmful to the organism. The mutations therefore are usually eliminated by purifying selection, which keeps the DNA sequence relatively unchanged over time. In nonfunctional regions of the genome, a mutation may have no impact and can persist in the genome without any consequences. These regions of the genome are said to evolve neutrally. Where G4s fall in this spectrum depends on their location in the genome.
“We can look at the patterns of change in a DNA sequence among human individuals and between humans and our close primate relatives as a test of natural selection and then use selection as an indicator of function,” said Yi-Fei Huang, assistant professor of biology at Penn State and a leader of the research team. “Our tests show that G4s located within functional regions of the genome appear to be under purifying selections, which is further evidence that G4s should be considered as functional elements. The only exception from this pattern were protein-coding regions of genes, where G4s are relatively uncommon, rather unstable, and do not evolve under purifying selection. G4s in protein-coding regions of genes might be nonfunctional and costly to maintain.”
The research team has recently shown that G4s, along with other types of non-B DNA, have increased mutation rates. The fact that G4s located outside of protein-coding regions are maintained by purifying selection, despite their high mutagenic potential, adds further weight to the evidence for classifying G4s as functional elements.
“We think that we are seeing evidence for a paradigm shift for how scientists define function in the genome,” said Kateryna Makova, Verne M. Willaman Chair of Life Sciences at Penn State and a leader of the research team. “First, geneticists focused almost exclusively on protein-coding genes, then we became aware of many functional non-coding elements, and now we have G4s and possibly other non-B DNA elements. Three-dimensional structure may be just as important for defining function as the underlying DNA sequence.”
“Defining the full complement of functional genome elements is crucial for interpreting the potential disease consequences not only of inherited genetic variants but also of mutations arising within tissues over the lifetime of individuals,” said Kristin Eckert, professor of pathology at the Penn State College of Medicine, co-author of the paper, and a member of the research team. “The identification of G4s as novel functional elements within the human genome is key to advancing the use of genetics in precision medicine.”
Story Source:
Materials provided by Penn State. Original written by Sam Sholtis. Note: Content may be edited for style and length.

Tests of a drug known to stimulate brain activity have shown early success in reducing symptoms of sluggish cognitive tempo in 38 men and women with attention deficit hyperactivity disorder (ADHD.)
A collection of symptoms including persistent dreaminess, fatigue, and slow-working speed, sluggish cognitive tempo has been a subject of debate over whether it is part of, or separate from, ADHD.
Researchers at NYU Grossman School of Medicine and Icahn School of Medicine at Mount Sinai who led the study say the stimulant lisdexamfetamine (sold as Vyvanse) reduced by 30 percent self-reported symptoms of sluggish cognitive tempo. It also lowered by over 40 percent symptoms of ADHD and significantly corrected deficits in executive brain function, with fewer episodes of procrastination, improvements in keeping things in mind, and strengthened prioritization skills.
Publishing in the Journal of Clinical Psychiatry online June 29, the study also showed that one-quarter of the overall improvements in sluggish cognitive tempo, such as feelings of boredom, trouble staying alert, and signs of confusion, were due to improvements in symptoms of ADHD.
The team interpreted that outcome to mean that decreases in ADHD-related incidents of physical restlessness, behaving impulsively, and/or moments of not paying attention were linked to some but not all of the improvements in sluggish cognitive tempo.
“Our study provides further evidence that sluggish cognitive tempo may be distinct from attention deficit hyperactivity disorder and that the stimulant lisdexamfetamine treats both conditions in adults, and when they occur together,” says lead study investigator and psychiatrist Lenard Adler, MD.
Adler, who directs the adult ADHD program at NYU Langone Health, says until now stimulants have only been shown to improve sluggish cognitive tempo symptoms in children with ADHD. The NYU Langone-Mount Sinai team’s findings, he adds, are the first to show that such treatments also work in adults.
A professor in the Departments of Psychiatry and Child and Adolescent Psychiatry at NYU Langone, Adler says sluggish cognitive tempo is likely a subset of symptoms commonly seen in some patients with ADHD and other psychiatric disorders. However, it remains unclear if sluggish cognitive tempo is a distinct psychiatric condition on its own and if stimulant medications will improve sluggish cognitive tempo in patients without ADHD.
Some specialists have been seeking to qualify sluggish cognitive tempo as distinct, but critics say more research is needed to settle the question.
“These findings highlight the importance of assessing symptoms of sluggish cognitive tempo and executive brain function in patients when they are initially diagnosed with ADHD,” says Adler.
For the study, funded by the drug manufacturer, Takeda Pharmaceuticals of Cambridge, Mass., several dozen volunteer participants received daily doses of either lisdexamfetamine or a placebo sugar pill for one month. Researchers then carefully tracked their psychiatric health on a weekly basis through standardized tests for signs and symptoms of sluggish cognitive tempo, ADHD, as well as other measures of brain function. Study participants then switched roles: The one-half who had been taking the placebo started taking daily doses of lisdexamfetamine, while the other half who had been on the drug during the study’s first phase started taking the placebo.
Adler has received grant and/or research support from Sunovion Pharmaceuticals, Enymotec, Shire Pharmaceuticals (now part of Takeda), Otsuka, and Lundbeck. He has also served as a paid consultant to these companies, in addition to Bracket, SUNY, the National Football League, and Major League Baseball. He has also received royalty payments since 2004 from NYU for adult ADHD diagnostic and training materials. All of these relationships are being managed in accordance with the policies and procedures of NYU Langone.

In a new paper published in the journal Vaccine: X, public health experts from Columbia University Mailman School of Public Health, the University of Oslo, and Spark Street Advisors highlight actions to accelerate access to vaccines globally. The paper reviews the vaccine research and development process and proposes areas where reforms could increase access, speed time to market and decrease costs — from R&D to manufacturing and regulation to the management of incentives like patents and public funding.
The COVID-19 pandemic has highlighted the importance of vaccines as public health and pandemic preparedness tools and amplified the importance of issues ranging from equitable distribution to reliable supply of quality, affordable vaccines. Delays in time from the first dose in a high-income country to introduction at scale in a low-income country can take years. These delays are driven by several challenges, some of which are unique to the vaccine development ecosystem. The authors write that the patenting and overall intellectual property (IP) protection are complex, regulatory oversight is rigorous, manufacturing processes require technical support or know-how transfer from the innovator, and market dynamics create obstacles to delivering at scale. To address these challenges, the authors propose several opportunities to accelerate the availability of vaccines in low and middle-income countries: Regulatory harmonization. Regulatory agencies around the world are increasingly recognizing the need to harmonize their approval process to enable efficiencies to save both time and money — something particularly important with regard to new technologies. For example, mRNA and DNA vaccines have the greatest potential of speeding the development processes and the recent approval of mRNA vaccine against COVID-19, brings promise for fully establishing regulatory pathways for these innovations. While mRNA vaccines do pose some challenges for low-income settings, in particular their requirement for ultra-cold storages, there are ongoing efforts to try to address this issue, including the establishment of a COVID-19 mRNA vaccine technology transfer hub. Manufacturing capacity building. In order for vaccines to be deployed quickly and at scale, manufacturing capacity must be in place to allow for sufficient scale up when demand is high. Given the substantial know-how required, access to facilities is not enough; low-income countries and regions must also have sufficient know-how about manufacturing processes. This will require freedom to operate around patents and investment in technology transfer. To face the unprecedented need and opportunity for rapid and massive worldwide availability of COVID-19 vaccines, new business models have emerged with agreements between originator companies and manufacturing companies operating in different geographical and market environments. Streamlined IP arrangements. With regard to IP arrangements, biopharmaceutical manufacturers and governments have made use of governmental compulsory licensing, patent oppositions, IP pools and voluntary IP licenses and technology transfer to advance access to new technologies. Although this has been limited in the field of vaccines, improving transparency and creating more streamlined IP arrangements, could contribute to increased diversity of supplier which will also help alleviate supply constraints.”The COVID-19 outbreak and steps that have been taken to speed time to market could act as a catalyst for other vaccines,” says senior author Nina Schwalbe, MPH, adjunct assistant professor of Population and Family Health. “While still very much a work in progress, the advancements demonstrated through the R&D of COVID-19 vaccines, give promise that many of the challenges to efficient and equitable vaccine development can be successfully addressed with adequate financing and political will.”
Co-authors include Ole Kristian Aars, Spark Street Advisors and University of Oslo; and Michael Clar, Spark Street Advisors. The research was supported in part with funding from the Medicines Patent Pool.
Story Source:
Materials provided by Columbia University’s Mailman School of Public Health. Note: Content may be edited for style and length.

Researchers from the Laboratory of Oncolytic-Virus-Immuno-Therapeutics (LOVIT) at the LIH Department of Oncology (DONC) are working on the development of novel anticancer strategies based on oncolytic viruses, “good” viruses that can specifically infect, replicate in and kill cancer cells. In particular, the LOVIT team elucidated the mechanism through which the H-1PV cancer-destroying virus can attach to and enter cancer cells, thereby causing their lysis and death. At the heart of this process lie laminins, and specifically laminin γ1, a family of proteins on the surface of a cancer cell to which this virus binds, and which therefore act as the ‘door’ through which the virus enters the cells. The findings, which were published in Nature Communications, carry significant implications for the advancement of virus-based anticancer strategies and for the prediction of a patient’s response to this innovative therapeutic approach.
Oncolytic viruses, such as the rat virus H-1PV, have the ability to selectively infect and kill tumour cells, inducing their lysis and stimulating an anticancer immune response, without however harming normal healthy tissues. Despite their notable clinical potential, their use as a standalone treatment does not currently result in complete tumour regression, mainly due to the varying degree of patient sensitivity and responsiveness. It is therefore important to be able to identify patients whose tumours display genetic characteristics that make them vulnerable to the virus and who are thus most likely to benefit from this novel anticancer therapy.
“In this context, we sought to elucidate the features of host cancer cells that enable oncolytic viruses to effectively infect and destroy them, focusing specifically on the factors required for cell attachment and entry,” says Dr Antonio Marchini, leader of LOVIT and corresponding author of the publication.
Using a technique known as RNA interference, the research team progressively ‘switched off’ close to 7,000 genes of cervical carcinoma cells to detect those that negatively or positively modulate the infectious capacity of H-1PV. They thus identified 151 genes and their resulting proteins as activators and 89 as repressors of the ability of H-1PV to infect and destroy cancer cells. The team specifically looked at those genes that coded for proteins localised on the cell surface, in order to characterise their role in determining virus docking and entry. They found that a family of proteins called laminins, and particularly laminin γ1, play a crucial role in mediating cell attachment and penetration. Indeed, deactivating the corresponding LAMC1 gene in glioma, cervical, pancreatic, colorectal and lung carcinoma cells resulted in a significant reduction in virus cell binding and uptake, and in increased cancer cell resistance to virus-induced death. A similar effect was observed when switching off the LAMB1 gene encoding the laminin β1 protein.
“Essentially, laminins at the surface of the cancer cell are the ‘door’ that allows the virus to recognise its target, attach itself and penetrate into it, subsequently leading to its destruction. In particular, the virus interacts with a specific portion of the laminin, a sugar called sialic acid, which is essential for this binding and entry process and for infection,” explains Dr Amit Kulkarni, first author of the publication.
The team went a step further and sought to assess the clinical implications of their findings for cancer patients. They found that laminins γ1 and β1 are differentially expressed across different tumours, being for instance overexpressed in pancreatic carcinoma and glioblastoma (GBM) cells compared to healthy tissues. Moreover, in brain tumours, their expression increases with tumour grade, with late-stage GBM displaying higher laminin levels than lower grade gliomas. Similarly, based on the analysis of 110 biopsies from both primary and recurrent GBM, the researchers reported significantly higher levels of laminins in recurrent GBM compared to primary tumours.
“These observations indicate that elevated laminin expression is associated with poor patient prognosis and survival in a variety of tumours, including gliomas and glioblastoma. The encouraging fact, however, is that cancers displaying high laminin levels are more susceptible to being infected and destroyed by the H-1PV virus and that patients with these tumours are therefore more likely to be responsive to this therapy,” adds Dr Marchini.
These findings could lead to the classification of cancer patients according to their individual laminin expression levels, thereby acting as a biomarker that predicts their sensitivity and responsiveness to H-1PV-based anticancer therapies. This will in turn allow the design of more efficient clinical trials with reduced costs and approval times and, ultimately, the development of enhanced combinatorial treatments to tangibly improve patient outcomes.
Story Source:
Materials provided by Luxembourg Institute of Health. Note: Content may be edited for style and length.

Globally, more than 400 million people have diabetes, most of them suffering from type 2 diabetes.
Before the onset of actual type 2 diabetes, people are often diagnosed with abnormalities in glucose metabolism that are milder than those associated with diabetes. The term used to indicate such cases is prediabetes. Roughly 5-10% of people with prediabetes develop type 2 diabetes within a year-long follow-up.
Insulin resistance in muscle tissue is one of the earliest metabolic abnormalities detected in individuals who are developing type 2 diabetes, and the phenomenon is already seen in prediabetes.
In a collaborative study, researchers from the University of Helsinki, the Helsinki University Hospital and the Minerva Foundation Institute for Medical Research investigated the link between skeletal muscle proteome and type 2 diabetes.
In the study, the protein composition of the thigh muscle was surveyed in men whose glucose tolerance varied from normal to that associated with prediabetes and type 2 diabetes. A total of 148 muscle samples were analysed.
The results were published in the iScience journal.

SharecloseShare pageCopy linkAbout sharingFrance has passed a law allowing single women and lesbian couples to get fertility treatment, currently reserved for heterosexual couples.The National Assembly (lower house) vote follows two years of heated debate and demonstrations by groups opposed to this expansion of reproductive rights.Many French women have gone to Belgium and Spain for fertility treatment, which can be very expensive.The new law brings France into line with 10 other EU countries and the UK.Besides Belgium and Spain, the 10 are: Denmark, Finland, Ireland, Luxembourg, Malta, the Netherlands, Portugal and Sweden. Outside the EU, Iceland and Norway have similar legal provisions.A recent Ifop opinion poll found 67% of French respondents favour the new law. There was resistance to it in the French Senate (upper house), and the draft acquired more than 1,500 amendments, but the National Assembly had the final say. It passed on Tuesday by 326 votes to 115, as President Emmanuel Macron’s party – La République en Marche (LREM) – has a lower house majority with its allies. Health Minister Olivier Véran said he hoped the first children would be conceived by the end of 2021, although changes to the law could be delayed by an appeal to France’s Constitutional Council involving opposition politicians on the right.

LaurieI was pregnant twice but lost the babies. Nature decided I need some medical assistance. I know now, even if I am sick, and even if I don’t find a man, one day I could have a childLaurieSingle nanny in ParisThe law will provide access to various fertility procedures, notably in vitro fertilisation (IVF) and artificial insemination, for all women under 43, with costs covered by the French health service.Children conceived with donor sperm will also be able to learn the donor’s identity when they become adults, removing the current French anonymity for donors.

LucieIt has been years since marriage equality passed in France. We had to wait until 2021 to have IVF equality. It’s a bittersweet victory because it has taken so long to get hereLucieParis journalist in lesbian relationshipIn 2018, there were 25,120 babies conceived through medically-assisted procreation (MAP) in France, after nearly 150,000 attempts, according to l’Assurance-maladie, the country’s national health insurance body. That was 3.3% of births.The new law also specifies that both the birth mother and her partner are to be named as the child’s parents on the birth certificate.French IVF bill sparks mass protests in ParisLesbian mums can’t register baby in Italy‘Three-person’ baby boy born in GreeceMagali Champetier, a lesbian mother quoted by La Dépêche newspaper, said “this law comes as a relief – we’ve been waiting a long time for it, and it’s already too late for many women because of the biological clock”.Her partner went to Spain in order to conceive two children through MAP. “I had to get married and wait a year before I could become the child’s legal parent. This [law] will remove that stress, and moreover the procedure will be free, unlike the treatment abroad.”Interviews by BBC OS on World Service radio.

Aerosol generated by playing woodwind and brass instruments is less than that produced when vocalising (speaking and singing) and is no different than a person breathing, new research has found. The findings, published online in the journal Aerosol Science and Technology, could be crucial to developing a roadmap for lifting COVID-19 restrictions in the performing arts, which have been significantly restricted since the start of the pandemic.
The research project, known as PERFORM (ParticulatE Respiratory Matter to InForm Guidance for the Safe Distancing of PerfOrmeRs in a COVID-19 PandeMic), was supported by Public Health England, the Department for Digital, Culture, Media and Sport (DCMS), and UKRI and was carried out by a collaborative team from Imperial College London, University of Bristol, Wexham Park Hospital, Lewisham and Greenwich NHS Trust and Royal Brompton Hospital.
The study looked at the amount of aerosols and droplets generated when playing woodwind and brass instruments compared with breathing and vocalisation (speaking and singing). The work was carried out in an environment with no background aerosol particles to complicate measurement interpretation, with nine musicians playing 13 woodwind and brass instruments.
The research team found aerosol (20 ?m diameter) were not observed during instrument playing but were observed during singing and coughing. Together the findings indicate that playing woodwind and brass instruments generates less aerosol than vocalising at high volume levels.
Concentrations of aerosol emissions from the musicians during breathing and vocalising were consistent with results from a study carried out last year of a large group of professional singers. No difference was found between the aerosol concentrations generated by professional and amateur performers while breathing or vocalising, suggesting aerosol generation is consistent across amateur and professional singers regardless of vocal training.
Dr Bryan Bzdek, Lecturer in the School of Chemistry at the University of Bristol and corresponding author on the paper, said: “Our study found playing woodwind and brass instruments generates less aerosol than vocalisation, which could have important policy implications in a roadmap to lifting COVID-19 restrictions, as many performing arts activities have been, and continue to be, severely restricted.”
Jonathan Reid, Director of Bristol Aerosol Research Centre and Professor of Physical Chemistry in the School of Chemistry at the University of Bristol, added: “This study confirms that the risks of transmission of SARS-CoV-2 are likely elevated during vocalisation at loud volume in poorly ventilated spaces. By comparison, playing wind instruments, like breathing, generates less particles that could carry the virus than speaking or singing.”
Story Source:
Materials provided by University of Bristol. Note: Content may be edited for style and length.

Six antibody characteristics could help scientists identify which pregnant women are at risk of placental malaria infections, finds a study published today in eLife.
Malaria infections can be devastating for pregnant mothers, particularly during their first pregnancies. If malaria parasites invade the placenta, they can starve babies of nutrition, potentially causing low birth weight, preterm deliveries, stillbirths, and pregnancy loss. But not all women are susceptible to placental malaria infections, and the new study may help clinicians to identify those at risk and researchers to develop new therapies to protect pregnant women from malaria and related complications.
A protein made by malaria parasites called VAR2CSA allows them to attach to placental cells and invade the placenta. “Many women produce antibodies that can prevent this infection, and even those who have placental malaria during their first pregnancy are less likely to become infected during subsequent pregnancies because they have already developed protective antibodies,” explains co-first author Dr Elizabeth Aitken, Research Officer at the Doherty Institute, University of Melbourne, Australia. “We set out to identify the features of these antibodies that help protect women from placental infections.”
In their experiments, the research team used a machine learning technique to identify naturally acquired antibody features mid pregnancy that were associated with protection from placental malaria at delivery. They analysed 169 antibody features in 77 pregnant women from Madang, Papua New Guinea.
Of these features, they identified six that were associated with placental malaria protection. These fell into two broad groups: those related to preventing the parasites from binding to placental cells, and those that led to the destruction of infected blood cells. “Using these features, we created a model that could predict which pregnant women would develop placental malaria infections with 86% accuracy,” says co-first author Timon Damelang, a PhD student at the Doherty Institute.
“These results suggest it is likely there are multiple pathways to protection against placental malaria,” adds co-first author Amaya Ortga-Pajares, also a PhD student at the Doherty Institute.
“It will be interesting to learn whether this same combination of features can protect pregnant women from placental malaria infections in other populations,” concludes senior author Professor Stephen Rogerson, Head of the Malaria Laboratory at the Doherty Institute, University of Melbourne. “This new insight is important for the development of novel vaccines or other treatments to protect pregnant women and their babies from the effects of malaria.”
Story Source:
Materials provided by eLife. Note: Content may be edited for style and length.

Neoadjuvant immune checkpoint blockade (ICB) is a promising treatment for melanoma and other cancer types, and has recently been shown to provide a modest survival benefit for patients with recurrent glioblastoma. To improve the treatment efficacy, researchers are looking for vulnerabilities in surgically removed glioblastoma tissues, but this has been difficult due to the vast differences within the tumor and between patients.
To address this challenge, researchers at Institute for Systems Biology (ISB) and their collaborators developed a new way to study tumors. The method builds mathematical models using machine learning-based image analysis and multiplex spatial protein profiling of microscopic compartments in the tumor.
The team used the approach to analyze and compare tumor tissues collected from 13 patients with recurrent glioblastoma and 23 patients with high-risk melanoma, with both sets of patients treated with neoadjuvant ICB. Using melanoma to guide the interpretation of glioblastoma analyses, they identified the proteins that correlate with tumor-killing T cells, tumor growth, and immune cell-cell interactions.
“This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade,” said Dr. Yue Lu, co-lead author of the paper describing the research.
“This framework can be used to uncover pathophysiological and molecular features that determine the effectiveness of immunotherapies,” added Dr. Alphonsus Ng, co-lead author of the paper.
The work was published today in Nature Communications, and is a collaborative project by ISB, UCLA and MD Anderson. Brain cancer represents one of the most challenging settings for achieving immunotherapy success. The fruitful collaboration between scientists and clinicians provides a tremendous opportunity for improving patient care and achieving an understanding of cancer immunotherapy at the deepest levels.
“We believe that the integrated biological, clinical and methodological insights derived from comparing two classes of tumors widely seen as at the opposite ends of the spectrum with respect to immunotherapy treatments should be of interest to broad scientific and clinical audiences,” said ISB President Dr. Jim Heath, corresponding author of the paper.
Story Source:
Materials provided by Institute for Systems Biology. Note: Content may be edited for style and length.

Researchers have identified a new treatment candidate that appears to not only halt neurodegenerative symptoms in mouse models of dementia and Alzheimer’s disease, but also reverse the effects of the disorders.
The team, based at Tohoku University, published their results on June 8 in the International Journal of Molecular Sciences. The treatment candidate has been declared safe by Japan’s governing board, and the researchers plan to begin clinical trials in humans in the next year.
“There are currently no disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer’s disease, Lewy body dementia, Huntington disease and frontotemporal dementia in the world,” said paper author Kohji Fukunaga, professor emeritus in Tohoku University’s Graduate School of Pharmaceutical Sciences. “We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases.”
In a previous study, the team found that the SAK3 molecule – the base structure of which is found in the enhancement of T-type Ca2+ channel activity – appeared to help improve memory and learning in a mouse model of Alzheimer’s disease.
According to previous studies, SAK3 enhances the function of a cell membrane channel thereby promoting neuronal activity in the brain. Typically, SAK3 promotes neurotransmitter releases of acetylcholine and dopamine that are significantly reduced in Alzheimer’s disease and Lewy body dementia. The Ca2+ channel enhancement is thought to trigger a change from resting to active in neuronal activity. When the Ca2+ channel is dysregulated in the brain, the acetylcholine and dopamine releases are reduced. The result is a dysregulated system that a person experiences as cognitive confusion and uncoordinated motor function.
SAK3 directly binds to the subunit of this channel, resulting in the enhancement of neurotransmission thereby improving cognitive deficits. The researchers found that the same process also appeared to work in a mouse model of Lewy body dementia, which is characterized by a build-up of proteins known as Lewy bodies.
“Even after the onset of cognitive impairment, SAK3 administration significantly prevented the progression of neurodegenerative behaviors in both motor dysfunction and cognition,” Fukunaga said.
In comparison, Aduhelm, the Alzheimer’s drug recently approved by the U.S. Food and Drug Administration, reduces the number of amyloid plaques in the brain, but it is not yet known if the amyloid reduction actually prevents further cognitive or motor decline in patients. According to Fukunaga, SAK3 helps destroy amyloid plaque – at least in mice.
SAK3 also helps manage the destruction of misfolded alpha-synuclein. Normal alpha-synuclein helps regulate neurotransmitter transmission in the brain. The protein can misfold and aggregate, contributing to what researchers suspect may be an underlying cause of neurodegenerative symptoms. This aggregation can also lead to the loss of dopamine neurons, which help with learning and memory.
“We found that chronic administration of SAK3 significantly inhibited the accumulation of alpha-synuclein in the mice,” Fukunaga said, noting that the mice received a daily oral dose of SAK3.
According to Fukunaga, SAK3 enhances the activity of the system that identifies and destroys misfolded proteins. In neurodegenerative diseases, this system is often dysfunctional, leaving misfolded proteins to muck up the cell’s machinery.
“SAK3 is the first compound targeting this regulatory activity in neurodegenerative disorders,” Fukunaga said. “SAK3 administration promotes the destruction of misfolded proteins, meaning the therapeutic has the potential to solve the problems of diverse protein misfolding diseases such as Parkinson’s disease, Lewy body dementia and Huntington disease, in addition to Alzheimer’s disease.” 
Story Source:
Materials provided by Tohoku University. Note: Content may be edited for style and length.