A molecule that shows promise in preventing Parkinson’s disease has been refined by scientists at the University of Bath and has the potential to be developed into a drug to treat the incurable neurodegenerative disease.
Parkinson’s disease is characterised by a specific protein in human cells ‘misfolding’, where it becomes aggregated and malfunctions. The protein – alpha-synuclein (αS) – is abundant in all human brains. After misfolding, it accumulates in large masses, known as Lewy bodies. These masses consist of αS aggregates that are toxic to dopamine-producing brain cells, causing them to die. It is this drop in dopamine signalling that triggers the symptoms of Parkinson’s, as the signals transmitting from the brain to the body become noisy, leading to the distinctive tremors seen in sufferers.
Previous efforts to target and ‘detoxify’ αS-induced neurodegeneration have seen scientists analyse a vast library of peptides (short chains of amino acids – the building blocks of proteins) to find the best candidate for preventing αS misfolding. Of the 209,952 peptides screened in earlier work by scientists at Bath, peptide 4554W showed the most promise, inhibiting αS from aggregating into toxic disease forms in lab experiments, both in solutions and on live cells.
In their latest work, this same group of scientists tweaked peptide 4554W to optimise its function. The new version of the molecule – 4654W(N6A) – contains two modifications to the parental amino-acid sequence and has proven to be significantly more effective than its predecessor at reducing αS misfolding, aggregation and toxicity. However, even if the modified molecule continues to prove successful in lab experiments, a cure for the disease is still many years away.
Dr Richard Meade, the study lead author, said: “Previous attempts to inhibit alpha synuclein aggregation with small molecule drugs have been unfruitful as they are too small to inhibit such large protein interactions. This is why peptides are a good option – they are big enough to prevent the protein from aggregating but small enough to be used as a drug. The effectiveness of the 4654W(N6A) peptide on alpha synuclein aggregation and cell survival in cultures is very exciting, as it highlights that we now know where to target on the alpha synuclein protein to supress its toxicity. Not only will this research lead to the development of new treatments to prevent the disease, but it is also uncovering fundamental mechanisms of the disease itself, furthering our understanding of why the protein misfolds in the first place.”
Read full paper in the Journal of Molecular Biology.
Release date: 09 December 2021
Source: University of Bath
SARS-CoV-2 protein interacts with Parkinson’s protein, promotes amyloid formation
Case reports of relatively young COVID-19 patients who developed Parkinson’s disease within weeks of contracting the virus have led scientists to wonder if there could be a link between the two conditions. Now, researchers reporting in ACS Chemical Neuroscience have shown that, at least in the test tube, the SARS-CoV-2 N-protein interacts with a neuronal protein called α-synuclein and speeds the formation of amyloid fibrils, pathological protein bundles that have been implicated in Parkinson’s disease.
In addition to respiratory symptoms, SARS-CoV-2 can cause neurological problems, such as loss of smell, headaches and “brain fog.” However, whether these symptoms are caused by the virus entering the brain, or whether the symptoms are instead caused by chemical signals released in the brain by the immune system in response to the virus, is still controversial. In Parkinson’s disease, a protein called α-synuclein forms abnormal amyloid fibrils, leading to the death of dopamine-producing neurons in the brain. Interestingly, loss of smell is a common premotor symptom in Parkinson’s disease. This fact, as well as case reports of Parkinson’s in COVID-19 patients, made Christian Blum, Mireille Claessens and colleagues wonder whether protein components of SARS-CoV-2 could trigger the aggregation of α-synuclein into amyloid. They chose to study the two most abundant proteins of the virus: the spike (S-) protein that helps SARS-CoV-2 enter cells, and the nucleocapsid (N-) protein that encapsulates the RNA genome inside the virus.
Release date: 14 December 2021
Source: American Chemical Society
Specific components of air pollution identified as more harmful than others
Ammonium is one of the specific components of fine particulate matter (PM2.5), that has been linked to a higher risk of death compared to other chemicals found in it, according to a new study in the journal Epidemiology.
Particulate matter is one of the most dangerous air pollutants – a complex mixture of extremely small particles and liquid droplets which can be directly emitted from natural sources, such as forest fires, or when gases emitted from power plants, industries and automobiles react in the air.
PM2.5 is airborne particulate matter smaller than 2.5 µm in diameter. It is usually believed the black carbon part of PM2.5 (mainly stemming from motorised vehicles) was the most harmful one. However, the team’s analysis of data in 210 cities across 16 countries from 1999-2017 found human health risks from air pollution vary depending on the proportion of different components in PM2.5.
One of the most dangerous components is ammonium (NH4+), originating mostly from fertiliser use and livestock. The risk of excess mortality from PM2.5 roughly increased from 0.6% to 1% when the proportion of ammonium increased from 1% to 20% in the mix1.
Cities with a larger concentration of ammonium in the mix, including Japanese cities Aikita, Aomori, Sendai, and Canadian cities London Ontario and Sarnia were associated with higher health risks. Specific action aimed at the agricultural and farming sectors may speed up the reduction of the negative health impacts of air pollution.
Release date: 16 December 2021
Source: London School of Hygiene & Tropical Medicine
Antibiotics Can Be First-Line Therapy for Uncomplicated Appendicitis Cases
With numerous recent studies demonstrating that antibiotics work as well as surgery for most uncomplicated appendicitis cases, the non-surgical approach can now be considered a routine option, according to a review article in JAMA.
“Acute appendicitis is the most common abdominal surgical emergency in the world, striking about one in 1,000 adults,” Pappas said. “Until recently, the only treatment option was surgery, so having a non-surgical approach for many of these cases has significant impact for both patients and the health care system.”
Pappas said the criteria for determining the best treatment approach is nuanced, but not excessively difficult. Appendicitis cases — marked by abdominal pain that often migrates to the lower right side, nausea and vomiting, and low-grade fever – are confirmed with ultrasound and/or CT scans.
Release date: 14 December 2021
Source: Duke University Medical Center
Common sleep disorder combo could be deadly
People who suffer from both insomnia and obstructive sleep apnoea are more likely to suffer from heart problems and are almost 50% more likely to die than those without either condition, say Flinders University researchers, who advise people being tested for one of the disorders be tested for the other.
Now, in a new study published in the European Respiratory Journal, Flinders researchers have studied a large US-based dataset of over 5000 people to understand the risks of COMISA.
The participants, aged around 60 years of age at the beginning of the study and 52% female, were followed for approximately 15 years, with 1210 people dying during that time.
The results suggested that participants with COMISA were two times more likely to have high blood pressure and 70% more likely to have cardiovascular disease than participants with neither insomnia nor sleep apnoea.
The study also showed participants with COMISA had a 47% increased risk of dying (for any reason) compared to participants with no insomnia or sleep apnoea, even when other factors known to increase mortality were taken into account.
Release date: 14 December 2021
Source: Flinders University
“Supermeres” may carry clues to cancer, Alzheimer’s disease and COVID-19
Researchers at Vanderbilt University Medical Center have discovered a nanoparticle released from cells, called a “supermere,” which contains enzymes, proteins and RNA associated with multiple cancers, cardiovascular disease, Alzheimer’s disease and even COVID-19.
The discovery, reported Dec. 9 in Nature Cell Biology, is a significant advance in understanding the role extracellular vesicles and nanoparticles play in shuttling important chemical “messages” between cells, both in health and disease.
For one thing, supermeres carry most of the extracellular RNA released by cells and which is found in the bloodstream. Among other functional properties, cancer-derived supermeres can “transfer” drug resistance to tumor cells, perhaps via the RNA cargo they deliver, the researchers reported.
Supermeres are important carriers of TGFBI, a protein that in established tumors promotes tumor progression. TGFBI thus may be a useful marker in liquid biopsies for patients with colorectal cancer, the researchers noted.
They also carry ACE2, a cell-surface receptor that plays a role in cardiovascular disease and is the target of the COVID-19 virus. This raises the possibility that ACE2 carried by supermeres could serve as a “decoy” to bind the virus and prevent infection.
Another potentially important cargo is APP, the amyloid-beta precursor protein implicated in the development of Alzheimer’s disease. Supermeres can cross the blood-brain barrier, suggesting that their analysis could improve early diagnosis or possibly even targeted treatment of the disease.
Release date: 10 December 2021
Source: Vanderbilt University Medical Center
Vaccines and previous infection could offer some “stronger than basic” protection to Omicron
One of the earliest, peer-reviewed studies looking into the Omicron variant of COVID-19 suggests that people previously infected with COVID, and those vaccinated, will have some, “stronger than basic” defense against this new strain of concern.
However, the test tube (or ‘in-vitro’, scientifically) samples of Omicron examined in this new research do show it “exceeds” all other variants in its potential capability to evade the protection gained from previous infection or vaccination.
Published inEmerging Microbes & Infections, the findings also suggest that although a third-dose enhancement strategy can “significantly boost immunity”, the protection from Omicron “may be compromised” – but more research is needed to better understand this.
Reporting on this very early study, lead author Youchun Wang, Senior Research Fellow from the National Institutes for Food and Drug Control in China, says their results support recent findings in South Africa which highlight Omicron was “easy to evade immunity”.
“We found the large number of mutations of the Omicron variant did cause significant changes of neutralization sensitivity against people who had already had COVID,” Wang says.
Release date: 12 December 2021
Source: Taylor & Francis Group
Are scientists homing in on a cure for Parkinson’s disease?
A molecule that shows promise in preventing Parkinson’s disease has been refined by scientists at the University of Bath and has the potential to be developed into a drug to treat the incurable neurodegenerative disease.
Parkinson’s disease is characterised by a specific protein in human cells ‘misfolding’, where it becomes aggregated and malfunctions. The protein – alpha-synuclein (αS) – is abundant in all human brains. After misfolding, it accumulates in large masses, known as Lewy bodies. These masses consist of αS aggregates that are toxic to dopamine-producing brain cells, causing them to die. It is this drop in dopamine signalling that triggers the symptoms of Parkinson’s, as the signals transmitting from the brain to the body become noisy, leading to the distinctive tremors seen in sufferers.
Previous efforts to target and ‘detoxify’ αS-induced neurodegeneration have seen scientists analyse a vast library of peptides (short chains of amino acids – the building blocks of proteins) to find the best candidate for preventing αS misfolding. Of the 209,952 peptides screened in earlier work by scientists at Bath, peptide 4554W showed the most promise, inhibiting αS from aggregating into toxic disease forms in lab experiments, both in solutions and on live cells.
In their latest work, this same group of scientists tweaked peptide 4554W to optimise its function. The new version of the molecule – 4654W(N6A) – contains two modifications to the parental amino-acid sequence and has proven to be significantly more effective than its predecessor at reducing αS misfolding, aggregation and toxicity. However, even if the modified molecule continues to prove successful in lab experiments, a cure for the disease is still many years away.
Dr Richard Meade, the study lead author, said: “Previous attempts to inhibit alpha synuclein aggregation with small molecule drugs have been unfruitful as they are too small to inhibit such large protein interactions. This is why peptides are a good option – they are big enough to prevent the protein from aggregating but small enough to be used as a drug. The effectiveness of the 4654W(N6A) peptide on alpha synuclein aggregation and cell survival in cultures is very exciting, as it highlights that we now know where to target on the alpha synuclein protein to supress its toxicity. Not only will this research lead to the development of new treatments to prevent the disease, but it is also uncovering fundamental mechanisms of the disease itself, furthering our understanding of why the protein misfolds in the first place.”
Read full paper in the Journal of Molecular Biology.
Release date: 09 December 2021
Source: University of Bath
A diet rich in plant-based products reduces the risk of cognitive impairment in the elderly
A diet rich in plant products reduces the risk of cognitive impairment and dementia in the elderly. This is the result of a study by the Biomarkers and Nutritional Food Metabolomics Research Group of the Faculty of Pharmacy and Food Sciences of the University of Barcelona (UB) and the CIBER on Frailty and Healthy Aging (CIBERFES).
The paper, published in the journal Molecular Nutrition & Food Research, is led by Cristina Andrés-Lacueva, professor at the Faculty of Pharmacy and Food Sciences and head of the Biomarkers and Nutritional Metabolomics of Food Research Group of the UB and the Biomedical Research Network Center in Frailty and Healthy Aging (CIBERFES), which is also part of the Food Innovation Network of Catalonia (XIA).
The results reveal a protective association between metabolites derived from cocoa, coffee, mushrooms and red wine, microbial metabolism of polyphenol-rich foods (apple, cocoa, green tea, blueberries, oranges or pomegranates) and cognitive impairment in the elderly.
The analysis of plasma samples indicated that some metabolites are related to the progression of cognitive impairment and dementia. As Professor Cristina Andrés-Lacueva explains, “for example, 2-furoylglycine and 3-methylanthine, which are biomarkers of coffee and cocoa consumption, had a protective profile, while saccharin –derived from the consumption of artificial sweeteners– is associated with a damaging role”.
Mercè Pallàs, professor at the Faculty of Pharmacy and Food Sciences and member of the Institute of Neurosciences (UBNeuro) of the UB, stresses that “the study of the relationship between cognitive impairment, the metabolism of the microbiota and food and endogenous metabolism is essential to develop preventive and therapeutic strategies that help to take care of our cognitive health”.
Release date: 09 December 2021
Source: University of Barcelona
New study shows link between long-term exposure to air pollution and liver disease
Metabolic-associated fatty liver disease (MAFLD) is a growing global health challenge and poses a substantial economic burden. A large-scale epidemiologic study in China has identified links between long-term exposure to ambient air pollution and MAFLD. These links are exacerbated by unhealthy lifestyles and the presence of central obesity, report scientists in the Journal of Hepatology, the official journal of the European Association for the Study of the Liver, published by Elsevier.
The incidence of MAFLD has increased steadily since the 1980s, currently affecting a quarter of the global population and a majority of patients with adult-onset diabetes and poses a substantial global burden. In Asia, MAFLD increased to 40% between 2012 and 2017. Formerly known as non-alcoholic fatty liver disease (NAFLD), it may progress to end-stage liver diseases such as cirrhosis and liver cancer, liver transplantation and liver-related death.
Release date: 06 December 2021
Source: EASL
Natural infection and vaccination together provide maximum protection against COVID variants
A combination of vaccination and naturally acquired infection appears to boost the production of maximally potent antibodies against the COVID-19 virus, new UCLA research finds.
The findings, published in the peer-reviewed journal mBio, raise the possibility that vaccine boosters may be equally effective in improving antibodies’ ability to target multiple variants of the virus, including the delta variant, which is now the predominant strain, and the recently detected omicron variant. (The study was conducted prior to the emergence of delta and omicron, but Dr. Otto Yang, the study’s senior author, said the results could potentially apply to those and other new variants.)
The researchers compared blood antibodies in 15 vaccinated people who had not been previously infected with SARS-CoV-2, the virus that causes COVID-19, with infection-induced antibodies in 10 people who were recently infected with SARS-CoV-2 but not yet vaccinated. Several months later, the 10 participants in the latter group were vaccinated, and the researchers then reanalyzed their antibodies. Most people in both of the groups had received the Pfizer–BioNTech or Moderna two-dose vaccines.
The scientists evaluated how antibodies acted against a panel of spike proteins with various common mutations in the receptor-binding domain, which is the target for antibodies that help neutralize the virus by blocking it from binding to cells.
They found that the receptor-binding domain mutations reduced the potency of antibodies acquired both by either natural infection or vaccination alone, to about the same degree in both groups of people. When previously infected people were vaccinated about a year after natural infection, however, their antibodies’ potency was maximized to a point that they recognized all of the COVID-19 variants the scientists tested.
Release date: 07 December 2021
Source: UCLA Health Sciences