Nitric oxide keeps stroke-damaged brain from repairing itself
Researchers at Sanford-Burnham Medical Research Institute in La Jolla, Calif., recently discovered that nitric oxide not only damages neurons, but it also inhibits the brain’s repair mechanisms, contributing to the severity and progression of numerous diseases (e.g., stroke, neurodegenerative conditions). The damaging effect is caused by nitric oxide binding to certain S-nitrosylated proteins involved in cell survival and lifespan, causing brain cells to die prematurely. Nitric oxide also inhibits the ERK1/2 signaling pathway through a reaction with the SHP-2 enzyme, interfering with a protective cascade of molecular events and blocking the brain’s ability to self-repair.
One-two punch strategy against bacteria and cancer
Cancer researchers at Rice University in Houston have come up with a new method to “confuse” cancer cells and drug-resistant bacteria. They suggest using a combination between a synthetic drug with a counterclockwise twist not found in nature (D-KLAKLAK-2) and clockwise-shaped natural toxins (KLAKLAK-2), with this molecular variability preventing cells from developing defense mechanisms. The drugs do not harm the animals’ own cells, but they penetrate and shred the double layered membranes of gram-negative bacteria, and, when tagged with special marker molecules, they can enter cancer cells and damage the mitochondria — structures remarkably similar to gram-negative bacteria. The advantages of this cocktail are that the drugs can be delivered in small doses, reducing the side effects, and they prevent bacteria and cancer form rapidly becoming resistant to the therapy.
Flip of a single molecular switch makes an old brain young
Yale School of Medicine researchers reported in the journal Neuron that they were able to reverse the single molecular switch that helps create the mature neuronal connections that bridge the gap between the adolescent and the adult brain. In essence, the researchers re-created a youthful mouse brain, proficient in both learning and healing processes. It all comes down to the Nogo Receptor 1 gene, which is required to suppress high levels of plasticity in the adolescent brain and to slow loss of memories. In mice without this gene, high levels of plasticity remain throughout adulthood, and blocking the gene in old mice resulted in a reset of the brain to its adolescent levels of plasticity. The effects were quick rehabilitation after injury, the mastering of complex motor tasks more quickly than adult mice with the receptor and the loss of stressful memories more quickly. Stephen Strittmatter, the senior author on the paper and an ASBMB member, said in a statement that the work “suggests we can turn back the clock in the adult brain and recover from trauma the way kids recover.”
Experimental therapy crosses blood-brain barrier to treat neurological disease
Scientists at Cincinnati Children’s Hospital Medical Center reported last month in the Proceedings of the National Academy of Sciences that they have engineered an experimental molecular therapy that crosses the blood-brain barrier and delivers large-molecule therapeutic agents to reverse neurological lysosomal storage disease in mice. This was achieved by merging a part of apolipoprotein E with a-L-idurondase, creating a therapeutic agent able to bind with endothelial cells from the capillaries involved in the blood-brain barrier and to cross it, thus reaching brain tissues in a dose-proportional manner. The levels of glycosaminoglycans and beta-hexosaminidase, previously altered by the lysosomal storage disease, were normalized. With continued treatment through hematopoietic stem cells therapy, this normalization persisted until the end of a five-month observation period.
Researchers identify salt as a trigger of autoimmune diseases
Researchers at Yale Medical School, Harvard Medical School and the Broad Institute reported in the March 6 issue of the journal Nature that they have identified dietary salt as a possible cause of increases in the incidence of autoimmune diseases. The researchers reported that salt can induce and worsen pathogenic immune system responses in mice and that the response is regulated by genes already involved in a variety of autoimmune diseases. T helper cells have been incriminated, particularly the Th17 cells, by yet-to-be-revealed mechanisms. “Once we have a more nuanced understanding of the development of the pathogenic Th17 cells, we may be able to pursue ways to regulate them or their function,” said Vijay Kuchroo, a senior scientist at Brigham and Women’s Hospital and a Broad Institute associate member.
Excess protein linked to development of Parkinson’s disease
Researchers at the University of California, San Diego, School of Medicine have discovered that overexpression of the protein alpha-synuclein (a gene product found in the inherited form of Parkinson’s disease) blocks necessary recycling processes in neurons, leading to progressive neuron degeneration and death. Writing in a recent issue of The Journal of Neuroscience, the researchers reported that they used serial block face scanning electron microscopy and other technologies to create three-dimensional images of the neocortex of transgenic mice engineered to over-express the human protein alpha-synuclein and noted hypertrophied presinaptic terminals. Normal degradation and recycling processes appeared to be hindered, progressively impairing the release of neurotransmitters and ultimately leading to neuron death. “I don’t think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD,” said principal investigator Mark H. Ellisman, director of the National Center for Microscopy and Imaging Research at UC San Diego and an ASBMB member.
USC scientists turn off the ability to feel cold
University of Southern California neuroscientists have identified the sensory network of neurons in the skin that relays the sensation of cold, managing to selectively shut off the ability to sense cold in mice, while still having them able to sense heat and touch. Writing in the Journal of Neuroscience, the researchers reported that they isolated and ablated neurons that express a protein called TRPM8, a sensor of cold temperatures in skin neurons, as well as a receptor for menthol. “One of our goals is to pave the way for medications that address the pain directly in a way that does not leave patients completely numb,” says David McKemy, associate professor of neurobiology at the USC Dornsife College of Letters, Arts and Sciences.
Self-assembling molecules offer new clues on life’s origins
Scientists at the Georgia Institute of Technology in Atlanta and the Institute for Research in Biomedicine in Barcelona reported that a pair of RNA-like molecules can spontaneously assemble into gene-length chains. The proto-RNA molecules used were cyanuric acid (CA) and triaminopyridine with a short chemical tail (TAPAS). The two bound to form rosettes that stacked atop one another, forming long genelike chains. The molecules were made up of as many as 18,000 individual TAPAS and CA components, with water as a solvent. Their findings were reported in the Journal of the American Chemical Society.
This news roundup was compiled by ASBMB Today contributor Teodora Donisan (firstname.lastname@example.org), a medical student at Carol Davila University in Bucharest, Romania. Send links of interest to email@example.com for possible inclusion in future issues.