Posts tagged protein
Articles and news from the latest research reports.
Solving Stem Cell Mysteries
The ability of embryonic stem cells to differentiate into different types of cells with different functions is regulated and maintained by a complex series of chemical interactions, which are not well understood. Learning more about this process could prove useful for stem cell-based therapies down the road. New research from a team led by Carnegie’s Yixian Zheng zeroes in on the process by which stem cells maintain their proper undifferentiated state. Their results are published in Cell October 26.
Embryonic stem cells go through a process called self-renewal, wherein they undergo multiple cycles of division while not differentiating into any other type of cells. This process is dependent on three protein networks, which guide both self-renewal and eventual differentiation. But the integration of these three networks has remained a mystery.
Using a combination of genetic, protein-oriented and physiological approaches involving mouse embryonic stem cells, the team—which also included current and former Carnegie scientists Junling Jia, Xiaobin Zheng, Junqi Zhang, Anying Zhang, and Hao Jiang—uncovered a mechanism that integrates all three networks involved in embryonic stem cell self-renewal and provide a critical missing link to understanding this process.
The key is a protein called Utf1. It serves three important roles. First, it balances between activating and deactivating the necessary genes to direct the cell toward differentiation. At the same time, it acts on messenger RNA that is the transcription product of the genes when they’re activated by tagging it for degradation, rather than allowing it to continue to serve its cellular function. Lastly, it blocks a genetic feedback loop that normally inhibits cellular proliferation, allowing it to occur in the rapid nature characteristic of embryonic stem cells.
Stimulating brain cells with light
Introducing a light-sensitive protein in transgenic nerve cells… transplanting nerve cells into the brains of laboratory animals… inserting an optic fibre in the brain and using it to light up the nerve cells and stimulate them into releasing more dopamine to combat Parkinson’s disease… These events may sound like science fiction but they are soon to become a reality in a research laboratory at Lund University in Sweden.
For the time being, this is basic research but the long term objective is to find new ways of treating Parkinson’s disease. This increasingly common disease is caused by degeneration of the brain cells producing signal substance dopamine.
Many experiments have been conducted on both animals and humans, transplanting healthy nerve cells to make up for the lack of dopamine, but it is difficult to study what happens to the transplant.
“We don’t know how the new nerve cells behave once they have been transplanted into the brain. Do they connect to the surrounding cells as they should, and can they function normally and produce dopamine as they should? Can we use light to reinforce dopamine production? These are the issues we want to investigate with optogenetics”, says Professor Merab Kokaia.
Optogenetics allows scientists to control certain cells in the brain using light, leaving other cells unaffected. In order to do this, the relevant cells are equipped with genes for a special light-sensitive protein. The protein makes the cells react when they are illuminated with light from a thin optic fibre which is also implanted in the brain. The cells can then be “switched on” when they are illuminated.
“If we get signals as a response to light from the host brain, we know that they come from the transplanted cells since they are the only ones to carry the light-sensitive protein. This gives us a much more specific way of studying the brain’s reactions than inserting an electrode, which is the current method. With an electrode, we do not know whether the electric signals that are detected come from “new” or “old” brain cells”, explains Merab Kokaia.
The work will be conducted on laboratory rats modelling Parkinson’s disease. The transplanted cells will be derived from skin from an adult human and will have been “reprogrammed” as nerve cells. Merab Kokaia will be collaborating with neuro-researchers Malin Parmar and Olle Lindvall on the project.
The three Lund researchers have received a grant of USD 75 000 from the Michael J. Fox Foundation, started by actor Michael J. Fox and dedicated to Parkinson’s research.
The light-sensitive protein is obtained from a bacterium, which uses light to gain energy. Since it is not a human protein, the safety checks will be extra strict if the method is to be used on humans.
”We know that this is long term research. But the methodology is interesting and it will be exciting to see what we can come up with,” says Merab Kokaia.
(Source: lunduniversity.lu.se)
Protein regulation linked to intellectual disability
Genetics researchers at the University of Adelaide have solved a 40-year mystery for a family beset by a rare intellectual disability - and they’ve discovered something new about the causes of intellectual disability in the process.
While many intellectual disabilities are caused directly by a genetic mutation in the so-called “protein coding” part of our genes, the researchers found that in their case the answer laid outside the gene and in the regulation of proteins.
Protein regulation involves the switching on or off of a protein by specific genes. As a consequence in this case, either too much or too little of this protein can trigger the disability.
The team has studied a large (anonymous) Australian family of 100 people, who for generations have not known the source of their genetically inherited condition.
The disability - which results in a lower IQ, behavioural problems such as aggression, and memory loss, and is linked with developmental delays, epilepsy, schizophrenia and other problems - affects only the male family members and can be passed on by the female family members to their children.
Genetic samples taken from the family and laboratory testing involving mice have confirmed that the protein produced by the HCFC1 (host cell factor C1) gene is the cause of this disability.
"The causes of intellectual disability generally are highly variable and the genetic causes in particular are numerous. The vast majority of intellectual disabilities are due to genetic mutations in proteins, so it was rather unexpected that we found this particular disability to be due to a regulatory mutation," says the leader of the study, Professor Jozef Gecz from the University of Adelaide’s School of Paediatrics and Reproductive Health.
"We’ve been researching this specific disability for 10 years and it’s taken us the last three years to convince ourselves that the protein regulation is the key," he says.
"For the family, this means we now have a genetic test that will determine whether or not a female member of the family is a carrier, which brings various benefits for the family.
"From a scientific point of view, this widens our viewpoint on the causes of these disabilities and tells us where we should also look for answers for those families and individuals without answers.
"This is just the tip of the iceberg in understanding the impact of altered gene regulation on intellectual disability - the gene regulatory landscape is much bigger than the protein coding landscape. We have already found, and I would expect to continue finding, a number of other intellectual disabilities linked with protein regulation over the next 20 years or so."
Professor Gecz and his team have published their findings in this month’s issue of the American Journal of Human Genetics.
(Source: adelaide.edu.au)
NIH researchers provide detailed view of brain protein structure
Results may help improve drugs for neurological disorders
Researchers have published the first highly detailed description of how neurotensin, a neuropeptide hormone which modulates nerve cell activity in the brain, interacts with its receptor. Their results suggest that neuropeptide hormones use a novel binding mechanism to activate a class of receptors called G-protein coupled receptors (GPCRs).
“The knowledge of how the peptide binds to its receptor should help scientists design better drugs,” said Dr. Reinhard Grisshammer, a scientist at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and an author of the study published in Nature.
Binding of neurotensin initiates a series of reactions in nerve cells. Previous studies have shown that neurotensin may be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth.
Dr. Grisshammer and his colleagues used X-ray crystallography to show what the receptor looks like in atomic detail when it is bound to neurotensin. Their results provide the most direct and detailed views describing this interaction which may change the way scientists develop drugs targeting similar neuropeptide receptors.
X-ray crystallography is a technique in which scientists shoot X-rays at crystallized molecules to determine a molecule’s shape and structure. The X-rays change directions, or diffract, as they pass through the crystals before hitting a detector where they form a pattern that is used to calculate the atomic structure of the molecule. These structures guide the way scientists think about how proteins work.
Neurotensin receptors and other GPCRs belong to a large class of membrane proteins which are activated by a variety of molecules, called ligands. Previous X-ray crystallography studies showed that smaller ligands, such as adrenaline and retinal, bind in the middle of their respective GPCRs and well below the receptor’s surface. In contrast, Dr. Grisshammer’s group found that neurotensin binds to the outer part of its receptor, just at the receptor surface. These results suggest that neuropeptides activate GPCRs in a different way compared to the smaller ligands.
Forming well-diffracting neuropeptide-bound GPCR crystals is very difficult. Dr. Grisshammer and his colleagues spent many years obtaining the results on the neurotensin receptor. During that time Dr. Grisshammer started collaborating with a group led by Dr. Christopher Tate, Ph.D. at the MRC Laboratory of Molecular Biology, Cambridge, England. Dr. Tate’s lab used recombinant gene technology to create a stable version of the neurotensin receptor which tightly binds neurotensin. Meanwhile Dr. Grisshammer’s lab employed the latest methods to crystallize the receptor bound to a short version of neurotensin.
The results published today are the first X-ray crystallography studies showing how a neuropeptide agonist binds to neuropeptide GPCRs. Nonetheless, more work is needed to fully understand the detailed signaling mechanism of this GPCR, said Dr. Grisshammer.
(Source: ninds.nih.gov)
New Diabetes Biomarkers Could Help Develop New Treatments
Researchers from the German Institute of Human Nutrition and the Max Delbrueck Center for Molecular Medicine recently revealed that they have been able to identify 14 new biomarkers for type 2 diabetes. The findings are important, as scientists believe that these biomarkers may be able to help in the development of new treatments to help prevent the disease. The scientists also believe that the results of the study will help them understand the various elements that contribute to the development of type 2 diabetes.
Scientists announce new treatment for type II diabetes
According to the World Health Organization, there are currently 347 million diabetics worldwide, with 90 percent of those people having type II diabetes specifically. It occurs when fat accumulates in places such as muscles, blood vessels and the heart, causing the cells in those areas to no longer be sufficiently responsive to insulin. This insulin resistance, in turn, causes blood glucose levels to rise to dangerous levels. Ultimately, it can result in things such as heart disease, strokes, blindness, kidney failure, and amputations. Fortunately, however, an international team of scientists has just announced a new way of treating the disease.
Currently, one of the main ways of treating type II diabetes involves switching the patient to a healthier diet and increasing the amount of exercise they get – the disease is most often caused by obesity. Additionally, oral medication can be used to increase insulin production and the body’s sensitivity to it, or to decrease glucose production. For approximately 30 percent of patients, however, such medication ceases to be effective after a few years, and they end up having to receive regular insulin injections.
The new treatment focuses on VEGF-B, a protein within the body that affects how fat is transported and stored. Using an antibody/drug known as 2H10, the scientists were able to block the signaling of VEGF-B in mice and rats, which subsequently kept fat from accumulating in the “wrong” areas of the animals – namely their muscles, blood vessels and hearts.
Understanding how salamanders grow new limbs provides insights into the potential of human regenerative medicine
By studying a real lizard-like amphibian, which can regenerate missing limbs, the Salk researchers discovered that it isn’t enough to activate genes that kick start the regenerative process. In fact, one of the first steps is to halt the activity of so-called jumping genes.
In research published August 23 in Development, Growth & Differentiation, and July 27 in Developmental Biology, the researchers show that in the Mexican axolotl, jumping genes have to be shackled or they might move around in the genomes of cells in the tissue destined to become a new limb, and disrupt the process of regeneration.
They found that two proteins, piwi-like 1 (PL1) and piwi-like 2 (PL2), perform the job of quieting down jumping genes in this immature tadpole-like form of a salamander, known as an axolotl - a creature whose name means water monster and who can regenerate everything from parts of its brain to eyes, spinal cord, and tail.
"What our work suggests is that jumping genes would be an issue in any situation where you wanted to turn on regeneration," says the studies’ senior author, Tony Hunter, a professor in the Molecular and Cell Biology Laboratory and director of the Salk Institute Cancer Center.
Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are characterised by the loss of nerve cells and the deposition of proteins in the brain tissue. A group of researchers led by Gabor G. Kovacs from the Clinical Institute of Neurology at the MedUni Vienna has now demonstrated that Alzheimer’s disease does not just – as previously believed – involve the proteins that are attributed to Alzheimer’s, but instead the condition can involve a mixture of interacting proteins from different neurodegenerative diseases.
“As a result, Alzheimer’s should not be treated in isolation. According to these latest findings, pure, classical Alzheimer’s disease, which involves only the attributed proteins tau and amyloid beta, appears not to be the norm,” says Kovacs. There is also a varied regional distribution of nerve cell loss and protein deposits between patients which, taken together, have clinical prognostic significance. As a consequence of this, differentiated strategies need to be developed for personalised therapy that takes account of all the interacting factors.
The new treatment concepts which are currently being developed by the MedUni Vienna’s neuropathologists, neurobiologists, neurologists, psychiatrists and neuroimaging experts will divide the patients into “sub-groups”. Says Kovacs: “The aim is to define these groups very precisely in future in order to be able to offer them personalised treatment.”
Dementia diseases: a growing trend
Around 100,000 Austrians are currently suffering from a dementia-related illness, according to statistics from the Austrian Alzheimer Society. According to estimates, this figure will rise to around 280,000 by 2050 as a result of the increasing age of the general population. Alzheimer’s disease is responsible for 60 to 80 per cent of these conditions.The global Alzheimer’s report by “Alzheimer’s Disease International” reckons that the prevalence of dementia doubles every 20 years. There are currently around 35 million people worldwide suffering a dementia-related illness. By 2030, their number will rise to 65.7 million and reach as many as 115.4 million by 2050.
Researchers at Cold Spring Harbor Laboratory (CSHL) have solved an important piece of one of neuroscience’s outstanding puzzles: how progenitor cells in the developing mammalian brain reproduce themselves while also giving birth to neurons that will populate the emerging cerebral cortex, the seat of cognition and executive function in the mature brain.
CSHL Professor Linda Van Aelst, Ph.D., and colleagues set out to solve a particular mystery concerning radial glial cells, or RGCs, which are progenitors of pyramidal neurons, the most common type of excitatory nerve cell in the mature mammalian cortex.
In genetically manipulated mice, Van Aelst’s team demonstrated that a protein called DOCK7 plays a central regulatory role in the process that determines how and when an RGC “decides” either to proliferate, i.e., make more progenitor cells like itself, or give rise to cells that will mature, or “differentiate,” into pyramidal neurons. The findings are reported in the September 2012 issue of Nature Neuroscience
Study reveal brain cells’ weakest links
People with degenerative neurological conditions could benefit from research that shows why their brain cells stop communicating properly.
Scientists believe that the findings could help to develop treatments that slow the progress of a broad range of brain disorders such as Huntington’s, Alzheimer’s and Parkinson’s diseases.
The team at the University, led by Professor Tom Gillingwater, analysed how connection points between brain cells break down during disease and identified six proteins that control the process.
Sending Signals
When connection points in the brain, known as synapses, stop working - because of injury or disease - the chain of brain signalling breaks down and cannot be repaired.
The research from The Roslin Institute and Centre for Integrative Physiology at the University will help scientists identify drugs that target these proteins.
This could eventually enable clinicians to slow the progress of these disorders.
This study has identified key proteins that may control what goes wrong in a range of brain disorders. We now hope to identify drugs that prevent the breakdown of communication between brain cells and, as a result, halt the progress of these devastating neurodegenerative conditions. — Dr Thomas Wishart Career Track Fellow, The Roslin Institute at the University
(Source: ed.ac.uk)