Posts tagged proteins
Articles and news from the latest research reports.
Scientists Map Initial Anti-Aging Formula
A new study indicates that scientists have found a new way of delaying the aging process in mice, and they hope to replicate the finding in people.
The scientists published their findings in the journal Cell Metabolism. The research was built upon an earlier study that shed light on progeria, a rare genetic disease that prematurely ages one in four million babies.
A mutation was found in the Lamin A protein, which lines the nucleus in human cells, disrupting the repair process and accelerating aging. They also found that normal and healthy Lamin A binds to and activates the gene SIRT1, which has been long associated with longevity. If scientists can develop drugs that mimic Lamin A or increase the binding between Lamin A and SIRT1, this may lead to anti-aging drugs.
The team also examined if the binding efficiency was boosted with resveratrol, a compound found in the skin of red grapes. Mice fed with concentrated resveratrol fared significantly better than healthy mice that weren’t given it and the onset of aging was delayed and the life expectancy was extended. Mice with progeria lived 30% longer when fed with resveratrol compared with progerial mice not given the compound.
Neurons die in Alzheimer’s because of faulty cell cycle control before plaques and tangles appear
The two infamous proteins, amyloid-beta (Aβ) and tau, that characterize advanced Alzheimer’s disease (AD), start healthy neurons on the road to cell death long before the appearance of the deadly plaques and tangles by working together to reactivate the supposedly blocked cell cycle in brain cells, according to research presented on Dec. 17 at the American Society for Cell Biology’s Annual Meeting in San Francisco.
Working in a mouse model of AD, George Bloom, PhD, of the University of Virginia (UVA) reports that neurons in AD start dying because they break the first law of human neuronal safety ⎯ stay out of the cell cycle.
Most normal adult neurons are permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. In contrast, AD neurons frequently re-enter the cell cycle but fail to complete mitosis, and ultimately die. By considering this novel perspective on AD as a problem of the cell cycle, Dr. Bloom and colleagues at UVA and at the University of Alabama, Birmingham, have discovered what they call an “ironic pathway” to neuronal cell death. The process requires the coordinated action of both Aβ and tau, which are the building blocks of plaques and tangles, respectively. Dr. Bloom’s results show just how toxic the two proteins can be even when free in solution and not aggregated into plaques and tangles.
Using mouse neurons grown in culture, the UVA researchers found that Aβ oligomers, which are small aggregates of just a few Aβ molecules each, induce the neurons to re-enter the cell cycle. Interestingly, the neurons must make and accumulate tau in order for this cell cycle re-entry to occur. The mechanism for this misplaced re-entry into the cell cycle requires that Aβ oligomers activate multiple protein kinase enzymes, each of which must then attach a phosphate to a specific site on the tau protein.
Following up on the cell culture results, Dr. Bloom and colleagues confirmed that Aβ-induced, tau-dependent cell cycle re-entry occurs in the brains of mice that were genetically engineered to mimic brains with human AD. The mouse brains were found to accumulate massive numbers of neurons that had transitioned from a permanent cell cycle stop, known as G0 (G zero), to G1, the first stage of the cell cycle, by the time they were 6 months old. Remarkably, otherwise identical mice that lacked functional tau genes showed no sign of cell cycle re-entry, confirming the cell culture results.
Neuronal cell cycle re-entry, a key step in the development of AD, can therefore be caused by signaling from Aβ through tau. Thus, Aβ and tau co-conspire to trigger seminal events in AD pathogenesis independently of their incorporation into plaques and tangles. Most important, Dr. Bloom believes that the activated protein kinases and phosphorylated forms of tau identified in this study represent potential targets for early diagnosis and treatment of AD.
(Source: eurekalert.org)
Better understanding of the cause of Alzheimer’s disease
Alzheimer’s disease is the most common form of dementia, affecting over 35 million people worldwide. It is generally assumed that the clumping of beta-amyloid (Aß) protein causes neuronal loss in patients. Medication focuses on reducing Aß42, one of the most common proteins and the most harmful. University of Twente PhD student Annelies Vandersteen is refining the current approach. She explains: “The results of my research provide a broader understanding of the processes that lead to Alzheimer’s disease and in this way may help to bring about new medication”.
The Aß protein occurs in the body in various lengths, ranging from 33 to 49 amino acids. The shorter varieties are regarded as ‘safe’, unlike the longer ones – Aß42 and longer – which are highly aggregating. Current therapeutic strategy tries to reduce the clumping of Aß42, and its harmful effects, by limiting the release of Aß42. Reducing Aß42 production at the same time results in a rise in Aß38 levels. Vandersteen comments: “One of the findings of my research is that small amounts of Aß38 can in fact increase or temper the clumping and toxic effects of longer Aß proteins. The processes that result in Alzheimer’s disease are determined by the whole spectrum of Aß proteins. So the picture is far less black and white than has been assumed so far, and less common forms of Aß are far less harmless than we thought.”
The study
Vandersteen examined the protein mixtures in a laboratory situation. She devised a series of experiments based on a computer-calculated hypothesis. The behaviour of the various Aß proteins and mixtures was studied in detail and described using various biophysical techniques. The influence of the various Aß proteins and mixtures on neurons was then studied in a cell culture.
(Source: alphagalileo.org)
In an article published online this week in the journal Nature, the UCSF team has identified the exact subset of nerve cells responsible for communicating gentle touch to the brains of Drosophila larvae—called class III neurons. They also uncovered a particular protein called NOMPC, which is found abundantly at the spiky ends of the nerves and appears to be critical for sensing gentle touch in flies.Without this key molecule, the team discovered, flies are insensitive to any amount of eyelash stroking, and if NOMPC is inserted into neurons that cannot sense gentle touch, those neurons gain the ability to do so.
“NOMPC is sufficient to confer sensitivity to gentle touch,” said Yuh Nung Jan, PhD, a professor of physiology, biochemistry and biophysics and a Howard Hughes Medical Institute investigator at UCSF. Jan led the study with his wife Lily Jan, PhD, who is also a UCSF professor and a Howard Hughes Medical Institute investigator.
The work sheds light on a poorly understood yet fundamental sense through which humans experience the world and derive pleasure and comfort.
Why is Touch Still Such a Mystery?
Scientists generally feel that, like those other senses, the sense of touch is governed by peripheral nerve fibers stretching from the spine to nerve endings all over the body. Special molecules in these nerve endings detect the mechanical movement of the skin surrounding them when it is touched, and they respond by opening and allowing ions to rush in. The nerve cell registers this response, and if the signal is strong enough, it will fire, signaling the gentle touch to the brain.
What has been missing from the picture, however, are the details of this process. The new finding is a milestone in that it defines the exact nerves and uncovers the identity of the NOMPC channel, one of the major molecular players involved—at least in flies.
Jan and his colleagues made this discovery through an unusual route. They were looking at the basic physiology of the developing fruit fly, examining how class III neurons develop in larvae. They noticed that when these cells developed in the insects, their nerve endings would always become branches into spiky “dendrites.”
Wanting to know what these neurons are responsible for, they examined them closely and found the protein NOMPC was abundant at the spiky ends. They then examined a fly genetically engineered to have a non-functioning form of NOMPC and showed that it was insensitive to gentle touch. They also showed that they could induce touch sensitivity in neurons that do not normally respond to gentle touch by inserting copies of the NOMPC protein into them.
(Image: Dietrich Meyer)
Alzheimer’s researcher reveals a protein’s dual destructiveness – and therapeutic potential
A scientist at the University of British Columbia and Vancouver Coastal Health has identified the molecule that controls a scissor-like protein responsible for the production of plaques – the telltale sign of Alzheimer’s disease (AD).
The molecule, known as GSK3-beta, activates a gene that creates a protein, called BACE1. When BACE1 cuts another protein, called APP, the resulting fragment – known as amyloid beta – forms tiny fibers that clump together into plaques in the brain, eventually killing neural cells.
Using an animal model, Dr. Weihong Song, Canada Research Chair in Alzheimer’s Disease and professor of psychiatry, found that disabling GSK3-beta’s effect in mice resulted in less BACE1 and far fewer deposits of amyloid in their brains. Song’s research, published online in the Journal of Clinical Investigation, also found that such mice performed better than untreated mice on memory tests.
Previous research had shown that GSK3-beta spurred the growth of twisted fibers inside neurons, known as tangles – another hallmark of AD. Song says his discovery of the protein’s dual destructiveness makes it a promising target for drug research.
GSK3-beta, however, is a versatile enzyme that controls many vital physiological functions. The drug used to inhibit GSK3-beta in the mice is too indiscriminate, and could cause several serious side effects, including cancer.
“If we can find a way to stop GSK3-beta’s specific reaction with BACE1, and still leave it intact to perform other crucial tasks, we have a much better chance of treating AD and preventing its progression,” says Song, a member of the Brain Research Centre at UBC and the Vancouver Coastal Health Research Institute (VCHRI), and Director of the Townsend Family Laboratories at UBC.
(Source: publicaffairs.ubc.ca)
Novel Antibodies for Combating Alzheimer’s and Parkinson’s Disease
Antibodies developed by researchers at Rensselaer Polytechnic Institute are unusually effective at preventing the formation of toxic protein particles linked to Alzheimer’s disease and Parkinson’s disease, as well as Type 2 diabetes, according to a new study.
The onset of these devastating diseases is associated with the inappropriate clumping of proteins into particles that are harmful to cells in the brain (Alzheimer’s disease and Parkinson’s disease) and pancreas (Type 2 diabetes). Antibodies, which are commonly used by the immune system to target foreign invaders such as bacteria and viruses, are promising weapons for preventing the formation of toxic protein particles. A limitation of conventional antibodies, however, is that high concentrations are required to completely inhibit the formation of toxic protein particles in Alzheimer’s, Parkinson’s, and other disorders.
To address this limitation, a team of researchers led by Rensselaer Professor Peter Tessier has developed a new process for creating antibodies that potently inhibit formation of toxic protein particles. Conventional antibodies typically bind to one or two target proteins per antibody. Antibodies created using Tessier’s method, however, bind to 10 proteins per antibody. The increased potency enables the novel antibodies to prevent the formation of toxic protein particles at unusually low concentrations. This is an important step toward creating new therapeutic molecules for preventing diseases such as Alzheimer’s and Parkinson’s.
“It is extremely difficult to get antibodies into the brain. Less than 5 percent of an injection of antibodies into a patient’s blood stream will enter the brain. Therefore, we need to make antibodies as potent as possible so the small fraction that does enter the brain will completely prevent formation of toxic protein particles linked to Alzheimer’s and Parkinson’s disease,” said Tessier, assistant professor in the Howard P. Isermann Department of Chemical and Biological Engineering at Rensselaer. “Our strategy for designing antibody inhibitors exploits the same molecular interactions that cause toxic particle formation, and the resulting antibodies are more potent inhibitors than antibodies generated by the immune system.”
Results of the new study, titled “Rational design of potent domain antibody inhibitors of amyloid fibril assembly,” were published online last week by the journal Proceedings of the National Academy of Sciences (PNAS).
How the animals lost their sensors
For free-living organisms, the ability to sense and respond to the outside environment is crucial for survival. Eukaryotes, such as animals and plants, often have highly complex network systems in place to monitor their surroundings and respond effectively, but bacteria have developed a remarkably simple system. It’s called the ‘Two Component System’ because it literally relies on just two components; a sensor and a responder. The sensor picks up the signal, communicates this to the responder, which then causes the effect.
The picture above shows this process happening. The ‘communication’ of the message from the sensor to the responder, as shown by the coloured arrows, is carried out by transferring phosphate molecules. The signal interacting with the sensor causes the sensor to autophosphorylate (phosphorylate itself) and then pass the phosphate molecule onto the responder to trigger the response. The letters “H” and “D” are the actual amino-acids being phosphorylated; Histadine and Aspartate.
Although Two-Component Systems (TCS) are found in all three superkingdoms of life (archaea, bacteria and eukaryotes) they are suspiciously absent from the animal kingdom. Plants have them, as do fungi and several protazoa, but they just aren’t present in animals. For this reason they’ve been looked into as potential antibiotic targets as knocking out the Two-Component Systems of most bacteria is fatal.
Why don’t animals use TCS? To answer this you have to start looking at the evolution of the system itself, because despite being nominally present in eukaryotes such as plants and fungi, TCS are used very differently. Bacteria use TCS for sensing a wide variety of signals; stress, metabolism, nutrient regulation, chemotaxis, pathogen-host interactions etc. In eukaryotes on the other hand they are used sparingly; for ethylene responses and photosensitivity in plants and osmoregulation in fungi and slime moulds.
Protein Test is First to Predict Rate of Progression in Lou Gehrig’s Disease
A novel test that measures proteins from nerve damage that are deposited in blood and spinal fluid reveals the rate of progression of amyotrophic lateral sclerosis (ALS) in patients, according to researchers from Mayo Clinic’s campus in Florida, Emory University and the University of Florida.
Their study, which appears online in the Journal of Neurology, Neurosurgery & Psychiatry, suggests this test, if perfected, could help physicians and researchers identify those patients at most risk for rapid progression. These patients could then be offered new therapies now being developed or tested.
ALS — also known as Lou Gehrig’s disease — is a progressive neurodegenerative disease caused by deterioration of motor neurons (nerve cells) that control voluntary muscle movement. The rate of progression varies widely among patients, and survival from the date of diagnosis can be months to 10 years or more, says Kevin Boylan, M.D., medical director of the ALS Clinic at Mayo Clinic in Florida.
"In the care of our ALS patients there is a need for more reliable ways to determine how fast the disease is progressing," says Dr. Boylan, who is the study’s lead investigator. "Many ALS researchers have been trying to develop a molecular biomarker test for nerve damage like this, and we are encouraged that this test shows such promise. Because blood samples are more readily collected than spinal fluid, we are especially interested in further evaluating this test in peripheral blood in comparison to spinal fluid."
There are no curative or even significantly beneficial therapies in clinics now for ALS treatment, but many are in development, Dr. Boylan says. A test like this could help identify those patients who are at risk for faster progression of weakness. With experimental treatments that primarily slow progression of ALS, detecting a treatment response in patients with faster progression may be easier to detect, says Dr. Boylan. Now, patients with varying rates of progression participate together in clinical studies, which can make analysis of a drug’s benefit difficult, he says.
"If there were a way to identify people who are likely to have relatively faster progression, it should be possible to conduct therapeutic trials with smaller numbers of patients in less time than is required presently," Dr. Boylan says.
A longer-range goal is to develop tests of this kind to gauge how well a patient is responding to experimental therapies, he adds.
The test measures neurofilament heavy form in blood and spinal fluid. These are proteins that provide structure to motor neurons, and when these nerves are damaged by the disease, the proteins break down and float free in blood serum and in the spinal fluid. Earlier research in this area was conducted by Gerry Shaw, Ph.D., a neuroscientist at the University of Florida, who is the study’s senior investigator and the developer of the neurofilament assay used in the study.
The researchers measured neurofilament heavy form in blood and spinal fluid samples from patients at Mayo Clinic and at Emory University, and correlated levels of the protein with rate of progression. “We demonstrated a solid association between higher levels of this protein and a faster progression of muscle weakness,” Dr. Boylan says. There was also evidence suggesting that ALS patients with higher protein levels may have shorter survival, he adds.
(Source: mayoclinic.org)
Research by scientists from the Centre for Brain Research at the University of Auckland has uncovered new information about the mechanisms underlying autism spectrum disorders (ASDs), to be published in the next issue of the prestigious Journal of Neuroscience.
Principal investigator, Dr Johanna Montgomery, says the findings are highly significant: “We’re moving beyond simply what happens in ASDs and starting to understand how it happens.”
The behavioural manifestations of ASDs are well documented and include impaired communication and socialisation, learning difficulties, and repetitive or stereotyped behaviours. These behavioural characteristics are in turn associated with a wide range of gene mutations. Many of these mutated genes are responsible for the production of specific proteins in the neurons of the brain.
Dr Montgomery and her team took a close look at parts of these neurons – the synapses, which are the structures that enable brain cells to communicate with each other. This cell to cell communication is vital for a healthy brain, and underlies how we learn, remember, move and sense.
In a complex cascade of chemical and electrical signalling, information is transmitted from one neuron to another at the synapses. This process is mediated by several families of protein, some of which form the bedrock of the synapse on the ‘listening’ side. Dr Montgomery’s team chose to investigate one of these proteins, known as Shank3, because it has been identified as vital to the communication process between two neurons, and because it is known to be mutated in ASDs.
Bacteria yield clues about why proteins go bad in ALS and Alzheimer’s
Scientists are unsure why proteins form improperly and cluster together in bunches, a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s and Mad Cow Disease. In the Nov. 1 issue of the journal Molecular Cell, Yale scientists shed light on protein aggregate formation by studying the process in bacteria.
“The question we are all asking is what happens when protein synthesis goes wrong?” said Jesse Rinehart, assistant professor of cellular and molecular physiology at Yale’s West Campus and co-senior author of the paper.
Proteins are created from instructions encoded in DNA and assembled in ribosomes within the cells. However, sometimes they are not assembled correctly, and these misfolded proteins tend to aggregate, a process typified by the plaques that form in the brains of Alzheimer’s patients.
The Yale team — led by Rinehart and Dieter Söll, Sterling Professor of Molecular Biophysics and Biochemistry and professor of chemistry — showed that the antibiotic streptomycin can trigger protein aggregations in the bacterium E. coli. Using large-scale proteomics and genetic screens, they analyzed the aggregates and searched for bacterial proteins that make E. coli cells resistant to antibiotics and other threats. The researchers discovered how one of these proteins protecting the bacteria from hydrogen peroxide also suppressed the aggregation of proteins triggered by streptomycin.