Research Roundup: Stressing Cells May Mitigate Dementia and Another Clue to Parkinson's Disease
Proteins are not static structures, they move and fold. In different shapes, they sometimes have different functions. And sometimes, when they misfold, they cause certain diseases, such as Creutzfeldt-Jakob disease (subacute spongiform encephalopathy), Alzheimer's, Parkinson's and others.
New research looked at how creating stress on cells appears to help alleviate misfolding, which seems to reverse the build-up of toxic protein aggregates by refolding them. For that and more research news, continue reading.
Stressing Cells to Mitigate Toxic Proteins in Dementia
Tangles of toxic proteins are associated with various dementias, such as beta-amyloid and tau in Alzheimer's disease. Often, these tangles are misfolded proteins. Researchers at the UK Dementia Research Institute, University of Cambridge identified a new mechanism that might reverse the build-up of these aggregates. They do this not by eliminating them completely but by refolding them. The research was published in Nature Communications.
The endoplasmic reticulum (ER) is a membrane structure found in mammalian cells that, among other things, synthesizes, folds, modifies and transports proteins to the surface or outside the cell. Their theory was that stressing the ER might cause protein misfolding and aggregation by diminishing the ER's ability to function correctly. But it was quite the reverse.
"We were astonished to find that stressing the cell actually eliminated the aggregates — not by degrading them or clearing them out, but by unraveling the aggregates, potentially allowing them to refold correctly," said Edward Avezov, Ph.D., who led the study. "If we can find a way of awakening this mechanism without stressing the cells — which could cause more damage than good — then we might be able to find a way of treating some dementias."
The process at least partly involves a class of proteins known as heat shock proteins. These proteins are created when cells are exposed to temperatures above their normal growth temperature and in response to stress.
One Reason Neurons Die in Parkinson's Disease
Scientists with the University of Cordoba have discovered, in mice, one of the reasons why dopamine-producing neurons die in Parkinson's disease. It has been understood that a protein called DJ1 was linked to Parkinson's, but not why until now. The researchers performed a comparative study of neurons in the brains of mice that have this active gene and ones that didn't. This absence or dysfunction of the gene expressing the DJ1 protein activated the cell cycle, causing cells to divide. Neurons don't have the capacity to divide, but they receive instructions to divide via the triggering of a cycle that, under normal conditions, doesn't occur. When the gene is altered, the neurons are forced into a division process they can't complete, which causes them to die and creates many Parkinson's symptoms.
Black Diamond Proves Platform in HER2 Mutations
There's good news this week for Cambridge, MA-based Black Diamond Therapeutics, and most importantly for patients with HER2-mutant cancers. On Thursday, the company announced the publication of a peer-reviewed paper highlighting 22 new oncogenic HER2 driver mutations identified and experimentally validated with its Mutation-Allostery-Pharmacology (MAP) discovery engine.
“At the core of our precision medicine approach to cancer treatment is the ability to identify new, full spectrum oncogenic mutations," Black Diamond CSO Elizabeth Buck said. "This study provides strong rationale for the power of our MAP discovery engine as we identified new oncogenic HER2 allosteric mutations that further suggest the need for novel treatment options."
The full paper can be found online in the American Association for Cancer Research (AACR)’s Cancer Research Journal.
Genomic Inversions More Common than Previously Thought
An inversion is when a segment of DNA or a genome is removed and reversed, essentially flipping its orientation. Researchers at EMBL Heidelberg in Germany, the University of Washington in the U.S., and Henrich Heine University in Dusseldorf, Germany, have demonstrated that inversions are among the most common mutational processes in humans. They described how inversions are formed in detail, focusing on a set of 40 inversions that repeatedly occur in the genome. They tend to occur in parts of the genome associated with certain human genomic disorders. Their research found that at least 0.6% of the genome in humans repeatedly changes direction. Clearly, the genome at these locations is not stable. These locations appear to be associated with disorders such as pediatric autism, developmental delay and epilepsy.
Amino Acid Proline Associated with Depression
Investigators with the Girona Biomedical Research Institute (IDIBGI) and Pompeu Fabra University (UPF) in Barcelona, Spain, identified the role of an amino acid in humans, mice and fruit flies suffering from depression. Did you know that fruit flies could suffer depression? Anyway, the amino acid is proline, which is present in different varieties of food. They found that consumption of a proline-rich diet was linked to a greater tendency to develop depression. They analyzed the type and amounts of amino acids in participants' diets, who also completed a questionnaire to measure their depressive mood. Proline concentration was one of the metabolites most linked with indicators of depression. But not everyone with a high proline intake was depressed. They also observed a link between depression and bacteria and depression and bacterial genes associated with proline metabolism. As such, circulating proline levels depended on the microbiota. Proline is quite common, however, found in beef, chicken, fish, cabbage, soy, peanuts, cucumber, chickpeas and numerous other foods.
Blood Tests to Determine Risk of Cytokine Storms in COVID-19
Researchers from the Infectious Disease Clinic, Azienda Sanitaria Universitaria Friuli Centrale, in Udine, Italy, presented research at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Lisbon, Portugal last month that identified a panel of cytokines that can be used to predict which COVID-19 patients are at risk of serious disease. Although it is known that cytokine storms are associated with COVID-19, it is not completely understood which cytokines drive it. Their research identified specific cytokines related to disease severity and was able to create a decision tree that allowed the prediction of patients at the greatest risk of a negative outcome. For example, high levels of IP-10 were associated with an excessive immune response that was tied to the patient likely to develop lung fibrosis and require intubation. Alternately, IL-6, a pro-inflammatory cytokine, was often accompanied by increased levels of sIL2Ra and IL-10, which have an anti-inflammatory role. In this case, immunosuppressive drugs typically used to treat severe COVID-19 could be more harmful than helpful.
Dr. Emanuela Sozia, M.D., who made the presentation, said, "It is not always possible to determine which COVID-19 patients have the worst prognosis, especially early on. It is becoming increasingly clear, however, that the earlier we treat excessive inflammation, the more likely we are to turn it off quickly and definitively and so avoid irreversible organ damage."