Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Gene-swap therapy eases rare brain disease
A new therapy that uses a virus to switch genes in the brain may help extend the lives of children with a rare and fatal neurodegenerative disorder. The results of the clinical trial, which began in 2001, show that the gene therapy cocktail conveyed into the brain by a molecular special delivery vehicle holds promise for children with Canavan disease.
As reported in Science Translational Medicine, the treatment uses a virus (adeno-associated virus, or AAV) as a “viral vector” meticulously tailored to enter the brain and safely switch good genes for bad.
“This was the first AAV-based gene therapy produced by a US academic institution to be approved for neurological use by the FDA,” says R. Jude Samulski, professor of pharmacology and director of the University of North Carolina Gene Therapy Center.
“It’s also the first vector produced by the university’s Gene Therapy Center Vector Core facility to go into patients.”
Children with Canavan disease have mutations in the ASPA gene that normally codes for an enzyme that helps the brain degrade N-acetyl-aspartate (NAA). The unregulated buildup of NAA is toxic to the brain’s gray matter, the protective myelin sheath surrounding nerve cells.
As the myelin deteriorates and neurons become unable to communicate, the child’s head size increases (macrocephaly), there are problems with movement, such as an inability to crawl, seizures occur, vision becomes impaired, and the children often die by age three. Fewer than 1,000 children in the US have the disorder.
Genetic manipulation of urate alters neurodegeneration in mouse model of Parkinson’s disease
A study by Massachusetts General Hospital researchers adds further support to the possibility that increasing levels of the antioxidant urate may protect against Parkinson’s disease. In their report published in PNAS Early Edition, the investigators report that mice with a genetic mutation increasing urate levels were protected against the kind of neurodegeneration that underlies Parkinson’s disease, while the damage was worse in animals with abnormally low urate.
"These results strengthen the rationale for investigating whether elevating urate in people with Parkinson’s can slow progression of the disease," says Xiqun Chen, MD, PhD, of the MassGeneral Institute for Neurodegenerative Diseases (MGH-MIND) and lead author of the PNAS report. “Our study is the first demonstration in an animal model that genetic elevation of urate can protect dopamine neurons from degeneration and that lowering urate can conversely exacerbate neurodegeneration.”
Characterized by tremors, rigidity, difficulty walking and other symptoms, Parkinson’s disease is caused by destruction of brain cells that produce the neurotransmitter dopamine. Healthy people whose urate levels are at the high end of the normal range have been found to be at reduced risk of developing Parkinson’s disease. Studies led by Michael Schwarzschild, MD, PhD, director of Molecular Neurobiology Laboratory at MGH-MIND, showed that, among Parkinson’s patients, symptoms appear to progress more slowly in those with higher urate levels. These observations led Schwarzschild and his colleagues to develop the SURE-PD (Safety of URate Elevation in Parkinson’s Disease) clinical trial, conducted at sites across the country through the support of the Michael J. Fox Foundation. Expected in early 2013, the results of SURE-PD will determine whether a medication that elevates urate levels should be tested further for its ability to slow the progression of disability in Parkinson’s disease.
Removing protein ‘garbage’ in nerve cells may help control 2 neurodegenerative diseases
Neuroscientists at Georgetown University Medical Center say they have new evidence that challenges scientific dogma involving two fatal neurodegenerative diseases — amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) — and, in the process, have uncovered a possible therapeutic target as a novel strategy to treat both disorders.
The study, posted online in the Journal of Biological Chemistry, found that the issue in both diseases is the inability of the cell’s protein garbage disposal system to “pull out” and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron.
"This finding suggests that if we’re able to ‘rev up’ that clearance machinery and help the cell get rid of the bad actors, it could possibly reduce or slow the development of ALS and FTD," says the study’s lead investigator, neuroscientist Charbel E-H Moussa, MB, PhD. "The potential of such an advance is very exciting." He cautions, though, that determining if this strategy is possible in humans could take many years and will involve teams of researchers.
The way to rev up protein disposal is to add parkin — the cell’s natural disposal units — to brain cells. In this study, Moussa and his colleagues demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43.”
Moussa says that his study further demonstrates that clumps known as “inclusions” of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued.
What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig’s disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia.
"In both diseases, TDP-43 is over-expressed or mutated, and the scientific debate has been whether loss of TDP-43 in the nucleus or gain of TDP-43 in the cytoplasm is the problem," Moussa says.
"Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed — without contributing to disease — and that TDP-43 in the nucleus is causing the damage," he says. "Because so much protein is being produced, the cell can’t keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem."
Moussa has long studied parkin, a molecule best known, when mutated and inactive, for its role in a familial form of Parkinson’s disease. He has studied it in Alzheimer’s disease and other forms of dementia. His hypothesis, which he has demonstrated in several recently published studies, is that parkin could help remove the toxic fragments of amyloid beta protein that builds up in the brains of Alzheimer’s disease patients.
What’s more, he developed a method to clear this amyloid beta when it begins to build up in neurons — a gene therapy strategy he has shown works in rodents. Work continues on this potential therapy.
In this study, Moussa found that parkin “tags” TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. “This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity,” he says.
"This discovery challenges the dogma that accumulation of TDP-43 in the cytoplasm is," Moussa says. "We think parkin is tagging proteins in the nucleus for destruction, but there just isn’t enough parkin around — compared with over-production of TDP-43 — to do the job."
Moussa says his next research steps will be to inject a drug that activates parkin to see whether that can prolong the lifespan and reduce motor defects in mice with ALS.
(Image: iStock)
Working with mice, Johns Hopkins scientists have discovered that a particular protein helps nerve cells extend themselves along the spinal cord during mammalian development. Their results shed light on the subset of muscular dystrophies that result from mutations in the gene that holds the code for the protein, called dystroglycan, and also show how the nerve and muscle failings of the degenerative diseases are related.
As mammals like mice and humans develop, nerve cells in the brain and spinal cord must form connections with themselves and with muscles to assure proper control of movement. Nerve cells sometimes extend the whole length of the spinal cord to connect sensory nerves bearing information, for example, from the legs to the brain. To do so, nerve cells anchor their “headquarters,” or cell bodies, in one location, and then extend a long, thin projection all the way to their target locations. These projections, or axons, can be 10,000 times longer than the cell body.
In a report published in the journal Neuron on Dec. 6, the authors suggest that, during fetal development, axons extend themselves along specific pathways created by dystroglycan.
European Project Aims To Create 1,500 New Stem Cell Lines
A joint public-private collaboration between the European Union and Europe’s pharmaceutical industry, called the StemBANCC project, will spend nearly 50 million euros to create 1,500 pluripotent stem cell lines. But the initiative’s goal isn’t to find a stem cell-based cure for diabetes or Alzheimer’s disease. They hope instead that their stem cell lines will prove to be faster and more effective drug screens in the search for drugs to fight these and other conditions.
A frustrating problem in medical research is the inadequacy of animal models. All too often a treatment works great in laboratory rats or mice but then its efficacy fails to repeat in human trials. But researchers are beginning to capitalize on the potential of stem cells – not as cures, but as means to finding cures.
Scientists are becoming more adept at turning skin cells into pluripotent stem cells, which can then be converted to other cell types such as neurons or heart cells. And because these are human cells they are superior to animal models for drug screening or toxicity testing. Human cell lines have been used for many years, but before pluripotent stem cells creating cell lines involved immortalizing the cells and thus drastically changing their physiology.
The goal of StemBANCC is to use these human-induced pluripotent stem cells as a drug discovery platform to treat the following 8 common diseases: Alzheimer’s disease, Parkinson’s disease, autism, schizophrenia, bipolar disorder, migraine, pain and diabetes. Studying these conditions typically involves creating an animal model, such as a rat that exhibits some behavioral hallmarks of autism after being given valproic acid. The cells from StemBANCC would improve upon animal models by providing, not only cells from humans but cells from patients with the actual disorders being studied. Skin cells gotten from a schizophrenia patient and converted (via pluripotency) to neurons, for instance, would give scientists a powerful tool with which to screen drugs.
Led by Oxford University, StemBANCC will involve 10 pharmaceutical companies and 23 academic institutions across 11 different countries. Part of the Innovative Medicines Initiative that pairs the European Union and the pharmaceutical industry. The EU is contributing 26 million euros ($33.5 million). Another 21 million euros ($27 million) are coming from the pharmaceutical industry. StemBANCC’s “kick-off” meeting took place in 2012 in Basel, Switzerland.
Zameel Cader, neurologist at the University of Oxford and a leader on the project, told Nature, “We’re specifically trying to develop a panel of lines across a range of diseases that are important to address. There isn’t another institution that’s doing this at the same scale across the same range of diseases.”
The hype surrounding stem cells typically extolls their virtues as a miraculous ‘cure all’ replacing damaged or diseased cells with new, healthy ones. And while stem cells have given blind people back part of their sight and have shown to restore some hearing in animals or even help paralyzed ones walk again in the lab, mainstream cures derived from stem cells are still rare. In the meantime, places like StemBANCC can pursue the less sexy, perhaps, but more reachable near term benefits of stem cells.
Turning urine into brain cells
Chinese researchers have devised a new technique for reprogramming cells from human urine into immature brain cells that can form multiple types of functioning neurons and glial cells. The technique, published in the journal Nature Methods, could prove useful for studying the cellular mechanisms of neurodegenerative conditions such as Alzheimer’s and Parkinson’s and for testing the effects of new drugs that are being developed to treat them.
Stem cells offer the hope of treating these debilitating diseases, but obtaining them from human embryos poses an ethical dilemma. We now know that cells taken from the adult human body can be made to revert to a stem cell-like state and then transformed into virtually any other type of cell. This typically involves using genetically engineered viruses that shuttle control genes into the nucleus and inserts them into the chromosomes, whereupon they activate genes that make them pluripotent, or able to re-differentiate into another type of cell.
In 2008, for example, American researchers took skin cells from an 82-year-old patient with amyotrophic lateral sclerosis and reprogrammed them into motor neurons. Cells obtained in this way could help us gain a better understanding of such diseases. Grafts of patients’ own cells do not elicit an immune response, so this approach may eventually lead to effective cell transplantation therapies. But it also has its problems – it appears that the reprogramming process destabilizes the genome and causes mutations, and that iPSCs may therefore harbour genetic defects that render them useless.
Last year, Duanqing Pei of the Chinese Academy of Sciences and his colleagues reported that human urine contains skin-like cells from the lining of the kidney tubules which can be efficiently reprogrammed, via the pluripotent state, into neurons, glia, liver cells and heart muscle cells. Now they have improved on the approach, making it quicker, more efficient and possibly less prone to errors.
In the new study, they isolated cells from urine samples given by three donors, aged 10, 25 and 37, and converted them directly into neural progenitors. They then grew these cells in Petri dishes and drove them to differentiate into mature neurons that can generate nervous impulses, and also into astrocytes and oligodendrocytes, two types of glial cell found in the human brain. Finally, they transplanted the re-programmed neurons and astrocytes into the brains of newborn rats, and found that the cells had survived when they examined the brains a month later, but it remains to be seen if they can survive for longer, and if they integrate into the existing circuits to be become functional.
This isn’t the first time that one type of cell has been converted into another without going through the pluripotent stage – in 2010, researchers from Stanford converted mouse connective tissue cells directly into neurons. The new technique does have a number of advantages, however.
Instead of using a virus to deliver the reprogramming genes, the researchers used a small circular piece of bacterial DNA which can replicate in the cytoplasm. This not only speeds up the process, but also eliminates the need to integrate the reprogramming genes into the chromosome, which is one potential source of genetic mutation, but it’s still not clear whether these cells contain fewer mutations than those reprogrammed using viruses.
Even so, the technique also makes the procedure of generating iPSCs far easier and non-invasive, as the cells can be obtained from a urine sample instead of a blood sample or biopsy. The next logical step will be to generate neurons from urine samples obtained from patients with Alzheimer’s, Parkinson’s, and other neurodegenerative diseases and to determine the extent to which this new non-viral technique damages the DNA.
(Source: Guardian)
Scientists Identify Two Genes Essential for Breathing
A team of researchers at the New York University’s Langone Medical Center has discovered that two genes, called Hoxa5 and Hoxc5, play a critical role in establishing the neuronal circuits required for breathing. The discovery could help advance treatments for spinal cord injuries and neurodegenerative diseases.
The three-year study published in the journal Nature Neuroscience identifies a molecular code that distinguishes a group of muscle-controlling nerve cells collectively known as the phrenic motor column (PMC).
“These cells lie about halfway up the back of the neck, just above the fourth cervical vertebra, and are probably the most important motor neurons in your body,” explained senior author Prof Jeremy Dasen of the Howard Hughes Medical Institute.
Harming the part of the spinal cord where the PMC resides can instantly shut down breathing. But relatively little is known about what distinguishes PMC neurons from neighboring neurons, and how PMC neurons develop and wire themselves to the diaphragm in the fetus. The PMC cells relay a constant flow of electrochemical signals down their bundled axons and onto the diaphragm muscles, allowing the lungs to expand and relax in the natural rhythm of breathing.
“We now have a set of molecular markers that distinguish those cells from other populations of motor neurons, so that we can study them in detail and look for ways to selectively enhance their survival,” Prof Dasen said.
See-through ‘MitoFish’ opens a new window on brain diseases
Scientists have demonstrated a new way to investigate mechanisms at work in Alzheimer’s and other neurodegenerative diseases, which also could prove useful in the search for effective drugs. For new insights, they turned to the zebrafish, which is transparent in the early stages of its life. The researchers developed a transgenic variety, the “MitoFish,” that enables them to see – within individual neurons of living animals – how brain diseases disturb the transport of mitochondria, the power plants of the cell.
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, ALS (amyotrophic lateral sclerosis), and MS (multiple sclerosis) are quite different in their effects on patients’ cognitive and motor functions, behavior, and prognosis. Yet on the level of individual neurons, common mechanisms can be observed that either cause or accompany nerve degeneration in a number of different diseases. One of these is a disturbance in the transport of mitochondria, organelles that play several vital roles in the life of a cell — above all, delivering energy where it is needed. And in a neuron, an extremely power-hungry cell, that means moving mitochondria all the way down its longest extension, the axon. Studying mitochondria transport in other animal models of neurodegenerative disease, particularly in mice, has been revealing. But the MitoFish model opens up new possibilities.
The new model was jointly developed in the labs of Prof. Thomas Misgeld of the Technische Universität München (TUM) and Dr. Bettina Schmid, a senior scientist of the German Center for Neurodegenerative Diseases (DZNE) based at the institute of LMU Prof. Christian Haass. “This collaboration has provided a system,” Misgeld says, “with which we can try to understand the traffic rules or the life cycle of a given organelle, in this case mitochondria, in the context of a nerve cell that’s existing in its physiological environment, where it is developing and changing. Most of these things we don’t understand well enough to model them in another setting, so we have the organism do it for us.”
The MitoFish is both readily manipulated, enabling researchers to pose specific questions, and literally transparent — allowing non-invasive in vivo observation of changes relevant to disease processes. It is possible to image a whole, living neuron over time and to follow the movements of mitochondria within it. “The zebrafish is an established genetic model,” Schmid explains, “which means you can bring foreign genes or certain proteins into a fish to test hypotheses about basic biology, disease mechanisms, or potential therapies. And because the early embryo is transparent, you can label specific nerve cells with a fluorescent protein and then look at them in an intact, living animal.”
Lipid metabolism regulates the activity of adult neural stem cells
Neural stem cells generate thousands of new neurons every day in two regions of the adult brain: the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus. This process, called adult neurogenesis, is critical for a number of processes implicated in certain forms of learning and memory. Impaired adult neurogenesis has been associated with a number of diseases such as depression, epilepsy, and Alzheimer’s disease.
A team led by Sebastian Jessberger, Professor of Neurosciences at the Brain Research Institute, has now identified a novel mechanism that plays a key role in adult neurogenesis and is required for the life-long activity of neural stem cells. Prof. Jessberger believes that “this finding will hopefully give us a new target to develop novel drugs against depression or neurodegenerative diseases”. The results of this study were published on December 2nd in the scientific journal Nature.
Stem cells produce their own lipids
Researchers in his group could show that stem cells depend on glucose-derived production of new fatty acids and lipids. When the key enzyme of this pathway, fatty acid synthase (Fasn), is blocked in neural stem cells, they loose their ability to divide which results in a reduction in newborn neurons.
To prevent the constant division of neural stem cells, this pathway is regulated by a protein called Spot14, which inhibits lipid synthesis. Controlling Fasn activity is important to make sure that stem cells do not divide too often, which could lead to a premature exhaustion or depletion of the stem cell pool. Surprisingly, the metabolic state of neural stem cells seems to be fundamentally distinct from their daughter cells (newborn neurons) and other dividing cells in the central nervous system. These other cell types are able to take up lipids from the blood stream and use them as important structural components of cell membranes but also for signaling events and as an energy source.
Potential target for new drugs
The study published by the Jessberger group has identified a novel target to pharmacologically enhance the activity of neural stem cells in diseases that are associated with reduced levels of newborn neurons, such as depression.
Marlen Knobloch, postdoc in the Jessberger lab and first author of the study, says: “Currently, we have to understand in much greater detail why neural stem cells are in this distinct metabolic state; to this end, we are currently performing experiments in the lab with the aim to enhance neurogenesis through manipulation of lipid metabolism”. However, one must not place too high expectations for the quick development of novel drugs, although for Simon Braun, co-first author of the study, “the hope certainly is to increase the number of newborn neurons by targeting lipid metabolism in the human brain”.
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).