Proteins are the workhorses of the cell, and their correctly folded three-dimensional structures are critical to cellular functions. Misfolded structures often fail to properly perform these vital jobs, leading to cellular stress and devastating neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease.In comparison with the mysteries of Alzheimer’s or Parkinson’s disease, Huntington’s disease has a seemingly simple culprit: an expansion in the polyglutamine (polyQ) tract of a protein called “Huntingtin” (Htt). This polyQ expansion causes the Htt protein to misfold, which triggers a cascade of events — including aggregation of the Htt protein into very stable, fibrillar, amyloid species, and ultimately, neuronal cell death.”Despite the simplicity of the misfolding involved, we understand very little about why Htt — an essential protein expressed ubiquitously in all human tissue — becomes so toxic when misfolded,” said Koning Shen, a grad student working in the Frydman Lab at Stanford University.Shen will describe her team’s multipronged efforts to gain a better understanding of the relationship between protein misfolding, aggregation and cell toxicity at the 58th Annual Biophysical Society Meeting, which takes place Feb. 15-19, 2014, in San Francisco, Calif.The cause of neuronal toxicity in Huntington’s disease remains unknown. Until recently, general consensus had associated fibrillar aggregates with pathogenesis in Huntington’s disease. Newer studies, however, point to transient, intermediate species called “oligomers,” which occur during the aggregation process, as the key players in neurotoxicity, rather than the fibrillar aggregates.”Identifying the toxic perpetrators will help explain the pathogenesis of not only Huntington’s disease, but perhaps Alzheimer’s and Parkinson’s as well,” explained Shen.Shen and colleagues also hope to discover which molecular factors may contribute to or ameliorate Htt toxicity. An extended polyQ region is the molecular signature of Htt aggregation, but regions flanking the polyQ tract can also alter the aggregation pathway.”A molecular chaperone called ‘TRiC’ can suppress Huntington’s disease pathogenesis by binding to one of the polyQ-flanking regions. These flanking regions act as a tool to probe the Htt aggregation pathway to learn how Htt forms toxic aggregate species and how the cell has developed tools to stop it,” Shen said. “Altering the regions flanking the polyQ tract could remarkably impact both the aggregation and toxicity of the Huntingtin protein.”Deletions or mutations within these regions may either exacerbate or alleviate aggregation — despite having the same polyQ length. And, Shen pointed out, “fibrillar aggregation and toxicity don’t go hand-in-hand amongst these flanking mutants. …Read more
Sep. 5, 2013 — Brown algae contain phlorotannins, aromatic (phenolic) compounds that are unique in the plant kingdom. As natural antioxidants, phlorotannins are of great interest for the treatment and prevention of cancer and inflammatory, cardiovascular and neurodegenerative diseases.Researchers at the Végétaux marins et biomolécules (CNRS/UPMC) laboratory at the Station biologique de Roscoff, in collaboration with two colleagues at the Laboratoire des sciences de l’Environnement MARin (Laboratory of Marine Environment Sciences) in Brest (CNRS/UBO/IFREMER/IRD) have recently elucidated the key step in the production of these compounds in Ectocarpus siliculosus, a small brown alga model species. The study also revealed the specific mechanism of an enzyme that synthesizes phenolic compounds with commercial applications. These findings have been patented and should make it easier to produce the phlorotannins presently used as natural extracts in the pharmaceutical and cosmetic industries. The results have also been published online on the site of the journal The Plant Cell.Until now, extracting phlorotannins from brown algae for use in industry was a complex process, and the biosynthesis pathways of these compounds were unknown. By studying the first genome sequenced from a brown alga, the team in Roscoff identified several genes homologous to those involved in phenolic compound biosynthesis in terrestrial plants (1). Among these genes, the researchers found that at least one was directly involved in the synthesis of phlorotannins in brown algae. They then inserted these genes into a bacterium, which thus produced a large quantity of the enzymes that could synthesize the desired phenolic compounds. One of these enzymes, a type III polyketide synthase (PKS III), was studied in detail and revealed how it produces phenolic compounds. …Read more
Aug. 14, 2013 — Two different versions of the same signaling protein tell a nerve cell which end is which, UA researchers have discovered. The findings could help improve therapies for spinal injuries and neurodegenerative diseases.University of Arizona scientists have discovered an unknown mechanism that establishes polarity in developing nerve cells. Understanding how nerve cells make connections is an important step in developing cures for nerve damage resulting from spinal cord injuries or neurodegenerative diseases such as Alzheimer’s.In a study published on Aug. 12 in the journal Proceedings of the National Academy of Sciences, UA doctoral student Sara Parker and her adviser, assistant professor of cellular and molecular medicine Sourav Ghosh, report that the decision which will be the “plus” and the “minus” end in a newborn nerve cell is made by a long and a short version of the same signaling molecule.Nerve cells — or neurons — differ from many other cells by their highly asymmetric shape: Vaguely resembling a tree, a neuron has one long, trunk-like extension ending in a tuft of root-like bristles. This is called the axon. From the opposite end of the cell body sprout branch-like structures known as dendrites. By connecting the “branches” of their dendrites to the “root tips” of other neurons’ axons, nerve cells form networks, which can be as simple as the few connections involved in the knee-jerk reflex or as complex as those in the human brain.Parker and her team found that embryonic nerve cells manufacture a well-known signaling enzyme called Atypical Protein Kinase C (aPKC) in two varieties: a full-length one and a truncated one. Both varieties compete to bind the same molecular partner, a protein called Par3. If the short form of aPKC pairs up with Par3, it tells the cell to grow a dendrite, and if the long one pairs up with Par3, it will make an axon instead.When the researchers blocked the production of the short form, the nerve cell grew multiple axons and no dendrites. …Read more
July 2, 2013 — Neurodegenerative diseases such as Alzheimer’s could be better understood thanks to insight into proteins linked to such conditions, a study suggests.Scientists studying thread-like chains of protein — called amyloid fibres — have found that low levels of these proteins may cause more harm to health than high levels.These rarely formed protein chains, which have been linked with dozens of diseases, are produced as a result of a genetic flaw or changes in body chemistry brought about by ageing.When this happens, short fibres are formed which become sticky and attract copies of themselves, forming an endless chain. These chains spontaneously break, creating more filament ends to which more proteins attach.In the context of neurodegenerative diseases, it is these short, broken pieces that seem to be most harmful, scientists say.Researchers have found that when protein levels are low, lots of short protein threads are formed. But when protein levels are high, this spontaneous breakage stops and most protein filaments remain long.Compared with harmful short protein fibres, long fibres do not appear to be damaging in the case of neurodegenerative diseases. Researchers therefore believe that high levels of the protein — which lead to these longer chains — may actually be protective.In addition to shedding light on disease, this insight into the protein chains may help scientists develop useful biomaterials, such as cell scaffolds, which are used for tissue engineering or to make artificial silk.Cait MacPhee, Professor of Biological Physics at the University of Edinburgh’s School of Physics and Astronomy, said; “We would expect that the higher the level of toxins, the worse the disease. However, in this study we found that the lower the level of the protein, the more of these damaging short fibres we see. Understanding how these protein chains form offers us insight not only into how diseases progress, but how we can produce controlled biomaterials for tissue engineering.”Read more
June 26, 2013 — Building on research published eight years ago in the journal Chemistry and Biology, Kenneth S. Kosik, Harriman Professor in Neuroscience and co-director of the Neuroscience Research Institute (NRI) at UC Santa Barbara, and his team have now applied their findings to two distinct, well-known mouse models, demonstrating a new potential target in the fight against Alzheimer’s and other neurodegenerative diseases.The results were published online June 4 as the Paper of the Week in the Journal of Biological Chemistry.Kosik and his research team focused on tau, a protein normally present in the brain, which can develop into neurofibrillary tangles (NFTs) that, along with plaques containing amyloid-ß protein, characterize Alzheimer’s disease. When tau becomes pathological, many phosphate groups attach to it, causing it to become dysfunctional and intensely phosphorylated, or hyperphosphorylated. Aggregations of hyperphosphorylated tau are also referred to as paired helical filaments.”What struck me most while working on this project was how so many people I’d never met came to me to share their stories and personal anxieties about Alzheimer’s disease,” said Xuemei Zhang, lead co-author and an assistant specialist in the Kosik Lab. “There is no doubt that finding therapeutic treatment is the only way to help this fast-growing population.” Israel Hernandez, a postdoctoral scholar of the NRI and UCSB’s Department of Molecular, Cellular and Developmental Biology, is the paper’s other lead co-author.Treatments for hyperphosphorylated tau, one of the main causes of Alzheimer’s disease, do not exist. Current treatment is restricted to drugs that increase the concentration of neurotransmitters to promote signaling between neurons.However, this latest research explores the possibility that a small class of molecules called diaminothiazoles can act as inhibitors of kinase enzymes that phosphorylate tau. Kosik’s team studied the toxicity and immunoreactivity of several diaminothiazoles that targeted two key kinases, CDK5/p25 and GSK3ß, in two Alzheimer’s disease mouse models. The investigators found that the compounds can efficiently inhibit the enzymes with hardly any toxic effects in the therapeutic dose range.Treatment with the lead compound in this study, LDN-193594, dramatically affected the prominent neuronal cell loss that accompanies increased CDK5 activity. Diaminothiazole kinase inhibitors not only reduced tau phosphorylation but also exerted a neuroprotective effect in vivo. In addition to reducing the amount of the paired helical filaments in the mice’s brains, they also restored their learning and memory abilities during a fear-conditioning assay.According to the authors, the fact that treatment with diaminothiazole kinase inhibitors reduced the phosphorylation of tau provides strong evidence that small molecular kinase inhibitor treatment could slow the progression of tau pathology. …Read more
June 17, 2013 — Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it’s approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University’s Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson’s disease.These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson’s and other neurodegenerative diseases. The research was funded by a grant from the Parkinson’s Disease Foundation and supported in part by the Lord Alliance Family Trust.Seeing a significant differenceAfter identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins’ ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the “climbing assay,” in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. …Read more
June 3, 2013 — In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.Dr. Boaz Barak of Tel Aviv University’s Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain’s activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.”This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain,” says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer’s. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer’s patient may help increase cognition and combat memory loss.A maze of memory lossThe researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. …Read more
May 29, 2013 — University of Texas Medical Branch at Galveston researchers have uncovered what may be a key molecular mechanism behind the lasting damage done by traumatic brain injury.
The discovery centers on a particular form of a protein that neuroscientists call tau, which has also been associated with Alzheimer’s disease and other neurodegenerative conditions. Under ordinary conditions, tau is essential to neuron health, but in Alzheimer’s the protein aggregates into two abnormal forms: so-called “neurofibrillary tangles,” and collections of two, three, or four or more tau units known as “oligomers.”
Neurofibrillary tangles are not believed to be harmful, but tau oligomers are toxic to nerve cells. They also are thought to have an additional damaging property — when they come into contact with healthy tau proteins, they cause them to also clump together into oligomers, and so spread toxic tau oligomers to other parts of the brain.
Now, in experiments with laboratory rats, using novel antibodies developed at UTMB, scientists have found that traumatic brain injuries also generate tau oligomers. The destructive protein assemblages formed within four hours after injury and persisted for at least two weeks — long enough to suggest that they might contribute to lasting brain damage.
Significantly, the rats used in the experiments were normal, unlike the genetically modified animals used in most tau research. The findings are thus likely to be more relevant to human traumatic brain injuries.
“Although people have given some attention to the formation of neurofibrillary tangles after traumatic brain injury, we were the first to look at tau oligomers, because we have an antibody that allows us to separate them out and see how much of the total tau is the toxic species,” said Bridget Hawkins, lead author of a paper on the research now online in the Journal of Biological Chemistry. “We saw that it’s a substantial amount — enough to play an important role in the effects of traumatic brain injury.”
Those effects can include memory deficits, which have been recently shown by UTMB researchers to be induced by tau oligomers. Other long-term ramifications of TBI include seizures, and disruptions in the sleep-wake cycle. The UTMB scientists hypothesize that these problems could be avoided if physicians had a way to stop the process of tau oligomerization.
One possibility is a treatment based on the antibodies used to label tau oligomers in this project, which were developed as part of an effort to develop a vaccine against different neurodegenerative disorders.
“We have antibodies that can specifically target these tau oligomers without interfering with the function of healthy tau,” said UTMB associate professor Rakez Kayed, the senior author on the paper. “This is a new approach — we’re starting by targeting them in animals — but we hope to eventually humanize these antibodies for clinical trials.”
Other authors of the paper include research associates Shashirekha Krishnamurthy and Urmi Sengupta, postdoctoral fellow Diana Castillo-Carranza, Dr. Donald Prough, Dr. George Jackson and Dr. Douglas DeWitt. Support for this research was provided by the Cullen Family Trust for Health Care, the Mitchell Center for Neurodegenerative Diseases and the Moody Center for Traumatic Brain and Spinal Cord Injury Research/Mission Connect.Read more