Posts tagged Huntington's disease
Articles and news from the latest research reports.
Promising approach to slow brain degeneration in a model of Huntington’s disease uncovered
Research presented by Dr. Lynn Raymond, from the University of British Columbia, shows that blocking a specific class of glutamate receptors, called extrasynaptic NMDA receptors, can improve motor learning and coordination, and prevent cell death in animal models of Huntington disease. As Huntington disease is an inherited condition that can be detected decades before any clinical symptoms are seen in humans, a better understanding of the earliest changes in brain cell (neuronal) function, and the molecular pathways underlying those changes, could lead to preventive treatments that delay the onset of symptoms and neurodegeneration. “After more than a decade of research on the pre-symptomatic phase of Huntington disease, markers are being developed to facilitate assessment of interventional therapy in individuals carrying the genetic mutation for Huntington disease, before they become ill. This will make it possible to delay onset of disease,” says Dr. Raymond. These results were presented at the 2014 Canadian Neuroscience Meeting, the 8th annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN), held in Montreal, May 25-28.
The neurotransmitter glutamate has long been known to promote cell death, and its toxic effects occur through the action of a family of receptors known as the NMDARs (N-methyl-D-Aspartate ionotropic glutamate receptors). Unfortunately, treating disorders of the nervous system by blocking NMDARs has not been successful because such treatments have numerous side effects. A recent hypothesis based on work from many scientists suggests that NMDARs located in different regions at the surface of neurons may have opposite effects, which would explain why blocking all NMDARs is not a good treatment option. A synapse is a structure that allows one neuron to connect to another neuron and pass an electrical or chemical signal between them. Many receptors for neurotransmitters are located in synapses, as these are the main area where these chemical signals are transmitted. However, receptors can also be found outside the synapse, and in this case are called extra-synaptic receptors. Many recent studies have revealed that NMDARs located at synapses act to increase survival signaling and promote learning and memory, whereas extra-synaptic NMDARs shut off survival signaling, interfere with learning mechanisms, and increase cell death pathways.
Dr. Raymond and her team were able, by using a drug that selectively blocks extra-synaptic NMDARs early, before the appearance of any symptoms, to delay the onset of Huntington-like symptoms in a mouse model of the disease. These promising results could lead to new treatment avenues for Huntington patients, and delay the appearance of symptoms. “The drug we used, memantine, is currently being used to treat moderate-stage Alzheimer disease patients. Our results suggest that clinical studies of memantine and similarly-acting drugs in Huntington disease, particularly in the pre-symptomatic stage, are warranted,”says Dr. Raymond.
Extra-synaptic NMDARs have also been shown to be involved in other neurodegenerative diseases, such as Alzheimer disease, and in damage caused by traumatic brain injury and some forms of stroke. These results therefore suggest novel treatment avenues for many conditions in which neurons degenerate and die, a new way to protect neurons before the appearance of symptoms of neurodegeneration.
(Source: eurekalert.org)
On the Defensive
TAU discovers that protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells
People diagnosed with Huntington’s disease, most in their mid-thirties and forties, face a devastating prognosis: complete mental, physical, and behavioral decline within two decades. “Mutant” protein clusters, long blamed for the progression of the genetic disease, have been the primary focus of therapies in development by pharmaceutical companies. But according to new research from Prof. Gerardo Lederkremer and Dr. Julia Leitman of Tel Aviv University’s Department of Cell Research and Immunology, in collaboration with Prof. Ulrich Hartl of the Max Planck Institute for Biochemistry, these drugs may not only be ineffective — they may pose a serious threat to patients.
In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington’s disease. On the contrary, these aggregates actually serve as a defense mechanism for “stressed” brain cells. Conducted on tissue cultures using cutting-edge microscopic technology, their studies identified a different causative agent — the “stress response” of affected brain cells.
"The upsetting implication for therapy of this disease is that drugs being developed to interfere with the formation of protein aggregates may in fact be detrimental," said Prof. Lederkremer. "The identification of the new cause will hopefully lead to the development of new therapeutic approaches. This may hold true for other neurodegenerative diseases as well."
Starting from genetic scratch
Prof. Lederkremer and his team chose to examine the effect of protein aggregates in the pathology of Huntington’s disease because its genetic cause is well-known, unlike those of other neurodegenerative diseases, such as Parkinson’s, whose origins remain less clear.
"What we found in this study — a surprise, although we suspected it — was that damage to the cells, the cell ‘stress’ that leads to death of cells, appeared well before the protein aggregates did," said Prof. Lederkremer. "And even more surprising, when the aggregates finally appeared, the stress was reduced, in some cases even stopping. The actual process of forming an aggregate was protective, isolating and segregating the problematic proteins. This explains why in autopsies of people who died of Huntington’s and other diseases like Alzheimer’s or old age, the protein aggregates in the brains were all quite similar, reflecting no specific disease link."
By interfering with the stress response of brain cells, rather than the formation of protein clusters, scientists may be able to slow, or even halt, the progression of neurodegenerative diseases. According to Prof. Lederkremer, this research paves the way for a revolutionary new direction for pharmaceutical research to treat Huntington’s, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases.
Response to stress
"The practical consequences are that several companies are already in advanced stages of development of drugs inhibiting this form of protein aggregate, interfering with the body’s natural process to protect the brain," said Prof. Lederkremer. "But the drugs should be focused on another area altogether, and the protein aggregates, a protective resource for the brain, should be left intact."
Samples of brain cells from mouse models afflicted with Huntington’s disease were examined using “live cell imaging,” the study of live cells through time-lapse microscopy. Prof. Lederkremer and his team were thus able to identify a compound that modified brain cells’ response to stress, promoting their survival.
"Our approach was to interfere with the stress response instead of the formation of the protein aggregates, and the lab succeeded in identifying a compound that altered the response, rescuing affected cells from death," said Prof. Lederkremer. "Our findings are most encouraging for the development of a therapy for this devastating disease, which is presently incurable."
(Source: aftau.org)
Unlocking a Mystery of Human Disease … in Space
Huntington’s disease is a grim diagnosis. A hereditary disorder with debilitating physical and cognitive symptoms, the disease usually robs adult patients of their ability to walk, balance, and speak. More than 15 years ago, researchers revealed the disorder’s likely cause—an abnormal version of the protein huntingtin; however, the mutant protein’s mechanism is poorly understood, and the disease remains untreatable.
Now, a new project led by Pamela Bjorkman, Max Delbrück Professor of Biology, will investigate whether the huntingtin protein can form crystals in microgravity aboard the International Space Station (ISS)—crystals that are crucial for understanding the molecular structure of the protein. The experiment was launched from Cape Canaveral in Florida on Friday, April 18 aboard the SpaceX CRS-3 cargo resupply mission to the ISS. On Sunday, April 20 the station’s robotic arm captured the mission’s payload, which included the proteins for Bjorkman’s experiment—which is the first Caltech experiment to take place aboard the ISS.
In the experiment, the researchers hope to grow a crystal of the huntingtin protein—the crystal would be an organized, latticelike arrangement of the protein’s molecules—which is needed to determine the molecular structure of the protein. However, molecules of the huntingtin protein tend to aggregate, or clump together, in Earth’s gravity. And this disordered arrangement makes it incredibly hard to parse the protein’s structure, says Gwen Owens, a graduate student in Bjorkman’s lab and a researcher who helped design the study.
"We need crystals for X-ray crystallography, the technique we use to study the protein, in which we shoot an X-ray through the protein crystal and analyze the organized pattern of radiation that scatters off of it," Owens says. "That pattern is what we depend on to identify the location of every carbon, nitrogen, and sulfur atom within the protein; if we shoot an X-ray beam at a clumped, aggregate protein—like huntingtin often is—we can’t get any data from it," she says.
Researchers have previously studied small fragments of crystallized huntingtin, but because of its large size and propensity to clumping, no one has ever successfully grown a crystal of the full-length protein large enough to analyze with X-ray crystallography. To understand what the protein does—and how defects in it lead to the symptoms of Huntington’s disease—the researchers need to study the full-length protein.
Looking for a solution to this problem, Owens was inspired by a few previous studies of protein formation on space shuttles and the ISS—studies suggesting that proteins can form crystals more readily in a condition of near-weightlessness called microgravity. “The previous studies looked at much simpler proteins, but we thought we could make a pretty good case that huntingtin would be an excellent candidate to study on the ISS,” Owens says.
They proposed such an experiment to the Center for the Advancement of Science in Space (CASIS), which manages U.S. research on the ISS, and it was accepted, becoming part of the first Advancing Research Knowledge, or ARK1, mission.
Because Owens and Bjorkman cannot travel with their proteins, and staff and resources are limited aboard the ISS, the crystal will be grown with a Handheld High-Density Protein Crystal Growth device—an apparatus that will allow astronauts to initiate growth of normal and mutant huntingtin protein crystals from a solution of protein molecules with just the flip of a switch.
As the crystals grow larger over a period of several months, samples will come back to Earth via the SpaceX CRS-4 return mission. The results of the experiment are scheduled to drop into the ocean just off the coast of Southern California—along with the rest of the return cargo—sometime this fall. At that point, Owens will finally be able to analyze the proteins.
"Our ideal result would be to have large crystals of the normal and mutant huntingtin proteins right away—on the first try," she says. After analyzing crystals of the full-length protein with X-ray crystallography, the researchers could finally determine huntingtin’s structure—information that will be crucial to developing treatments for Huntington’s disease.
Huntington’s disease: Study discovers potassium boost improves walking in mouse model
Tweaking a specific cell type’s ability to absorb potassium in the brain improved walking and prolonged survival in a mouse model of Huntington’s disease, reports a UCLA study published March 30 in the online edition of Nature Neuroscience. The discovery could point to new drug targets for treating the devastating disease, which strikes one in every 20,000 Americans.
Huntington’s disease is passed from parent to child through a mutation in the huntingtin gene. By killing brain cells called neurons, the progressive disorder gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. No cure exists, and patients with aggressive cases can die in as little as 10 years.
The laboratories of Baljit Khakh, a professor of physiology and neurobiology, and Michael Sofroniew, a professor of neurobiology, teamed up at the David Geffen School of Medicine at UCLA to unravel the role played in Huntington’s by astrocytes—large, star-shaped cells found in the brain and spinal cord.
Staying ahead of Huntington’s disease
Huntington’s disease is a devastating, incurable disorder that results from the death of certain neurons in the brain. Its symptoms show as progressive changes in behavior and movements.
The neurodegenerative disease is caused by a defect in the huntingtin gene (Htt) that causes an abnormal expansion in a part of DNA, called a CAG codon or triplet that codes for the amino acid glutamine. A healthy version of the Htt gene has between 20 and 23 CAG triplets. The mutational expansion in Htt can lead to long repeats of the CAG triplet, resulting in the mutant protein having a long sequence of several glutamine residues called a polyglutamine tract. This CAG triplet expansion in unrelated genes is the root of at least nine neurodegenerative disorders, including Huntington’s disease.
Rohit Pappu, PhD, professor of biomedical engineering at Washington University in St. Louis, and his colleagues in the School of Engineering & Applied Science and in the School of Medicine, are working to understand how expanded polyglutamine tracts form the types of supramolecular structures that are presumed to be toxic to neurons – a feature that polyglutamine expansions share with proteins associated with Alzheimer’s disease and Parkinson’s disease.
In recent work, Pappu and his research team showed that the amino acid sequences on either side of the polyglutamine tract within Htt can act as natural gatekeepers because they control the fundamental ability of polyglutamine tracts to form structures that are implicated in cellular toxicity. The results were published in PNAS Early Edition Nov.25.
“These are progressive onset disorders,” Pappu says. “The longer the polyglutamine tract gets, the more severe the disease, and the symptoms worsen with age. Our results are exciting because it means that any success we have in mimicking the effects of naturally occurring gatekeepers would be a significant step forward. And mechanistic studies are important in this regard because they enable us to learn from nature’s own strategies.
“Previous studies from other labs showed that the toxic effects of polyglutamine expansions are tempered by the sequence contexts of polyglutamine tracts in Htt, not just the lengths of the polyglutamine tracts”, Pappu says.
He and his research team focused on understanding the effects of sequence stretches that lie on either side of the polyglutamine tract in Htt. The results show that the N-terminal stretch accelerates the formation of ordered structures that are presumed to be benign to cells, whereas the C-terminal stretch slows the overall transition into structures that are expected to create trouble for cells, suggesting that these naturally occurring sequences behave as gatekeepers.
“It appears that where polyglutamine stretches are of functional importance, nature has ensured that they are flanked by gatekeeping sequences,” Pappu says.
Pappu and his team are now working to find way s to mimic the effects of the N- and C-terminal flanking sequences from Htt. His team is working closely with Marc Diamond, MD, the David Clayson Professor of Neurology at the School of Medicine, to understand how naturally occurring proteins interact with flanking sequences and see if they can coopt them to ameliorate the toxic functions in the polyglutamine expansions.
(Source: engineering.wustl.edu)
New therapeutic target identified for Huntington’s disease
A new study published 26th November in the open access journal PLOS Biology, identifies a new target in the search for therapeutic interventions for Huntington’s disease – a devastating late-onset neurodegenerative disorder.
The disease is genetic, affecting up to one person in 10,000, and from the age of about 35 leads to increasingly severe problems with movement, mental function, and behavior. Patients usually die within 20 years of onset, and there is to date no treatment that will modify the disease onset or progression.
Huntington’s disease is caused by an unusual type of mutation in a gene that encodes the “huntingtin” protein. These mutations create long stretches of the amino acid glutamine within the protein chain, preventing huntingtin from folding properly and making it more ‘sticky’. This causes huntingtin proteins to self-aggregate in both the nucleus and cytoplasm of cells, disrupting multiple aspects of cellular function and ultimately leading to the progressive death of nerve cells.
Nuclear huntingtin aggregates have been found to interfere with the transcription of many genes, and previous work has shown beneficial effects for Huntington’s disease of inhibiting a family of enzymes that are normally thought to regulate transcription – the histone deacetylases, or HDACs. However, humans have eleven different HDAC enzymes, and it’s been uncertain exactly which HDAC needs to be inhibited to see these benefits.
The new study from Michal Mielcarek, Gillian Bates and colleagues at King’s College London has pinpointed just one of these enzymes as the target – HDAC4 – but with an intriguing twist; everything is happening in the cytoplasm, not the nucleus, and HDAC4’s classic role in transcription has little to do with it.
The researchers noted that the HDAC4 protein naturally contains a region that, like mutant huntingtin, is rich in the amino acid glutamine. They show that HDAC4 can associate directly with huntingtin protein in a manner that depends on the length of the glutamine tracts, but that this association between HDAC4 and huntingtin occurs in the cytoplasm of nerve cells in the mouse brain, and – surprisingly – not in the nucleus, where HDAC4 is known to have its transcriptional role.
Bates and colleagues did their work in an aggressive disease mouse model of Huntington’s disease – the gold standard model for this type of study. They find that halving the levels of HDAC4 in the cells of Huntington’s disease mice can delay the aggregation of huntingtin in the cytoplasm, thereby identifying a new route to modulating the toxicity of mutant huntingtin protein. Crucially, reducing HDAC4 levels can also rescue the overall function of nerve cells and their synapses, with corresponding improvements seen in coordination of movement, neurological performance and lifespan of the mice. In agreement with the cytoplasmic association between HDAC4 and huntingtin, this all happens without any obvious improvement in the defective gene transcription in the nucleus.
There are currently no disease-modifying therapeutics available for Huntington’s disease. It is still very early days and it is important to note that the medical applications of any therapy arising from this study have not been studied in a clinical setting and are far from clear. However, one broad-brush HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) had previously been shown to improve movement defects in preclinical tests in this mouse model. The authors have shown in a related publication that, in addition to inhibiting HDAC enzyme function, SAHA decreases levels of the HDAC4 protein. Therefore it is hoped that the development of HDAC4-targeted compounds may be a promising strategy in improving the lot of Huntington’s disease patients.
(Source: eurekalert.org)
Yeast, human stem cells drive discovery of new Parkinson’s disease drug targets
Using a discovery platform whose components range from yeast cells to human stem cells, Whitehead Institute scientists have identified a novel Parkinson’s disease drug target and a compound capable of repairing neurons derived from Parkinson’s patients.
The platform—whose effectiveness is described in dual papers published online this week in the journal Science—could accelerate the discovery of drug candidates that address the underlying pathology of Parkinson’s and other neurodegenerative diseases. Today, no such drugs exist.
Parkinson’s disease (PD) and such neurodegenerative diseases as Huntington’s and Alzheimer’s are characterized by protein misfolding, resulting in toxic accumulations of proteins in the cells of the central nervous system. Cellular buildup of the protein alpha-synuclein, for example, has long been associated with PD, making this protein a seemingly appropriate target for therapeutic intervention.
In the search for compounds that might alter a protein’s behavior or function—such as that of alpha-synuclein—drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they’re moved from the in vitro environment into a living setting.
To overcome this limitation, the lab of Whitehead Member Susan Lindquist has turned to phenotypic screens in which candidate compounds are studied within a living system. In Lindquist’s lab, yeast cells—which share the core cell biology of human cells —serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.
“Phenotypic screens are probably underutilized for identifying drug targets and potential compounds,” says Daniel Tardiff, a scientist in the Lindquist lab and lead author of one of the Science papers. “Here, we let the yeast tell us what is a good target. We let a living cell tell us what’s critical for reversing alpha-synuclein toxicity.”
In a screen of nearly 200,000 compounds, Tardiff and collaborators identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. Enabled by the chemistry provided by Nate Jui in the Buchwald lab at MIT, Tardiff found that the compound was working by restoring functions mediated by a cellular protein critical for trafficking that was previously thought to be “undruggable.”
But would these findings apply in human cells? To answer that question, husband-and-wife team Chee-Yeun Chung and Vikram Khurana led the second study published in Science to examine neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson’s patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. To ensure that any pathology developed in the cultured neurons could be attributed solely to the genetic defect, the researchers also derived control neurons from iPS cells in which the mutation had been corrected.
Chung and Khurana used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens in Tardiff’s study reversed the damage in these neurons.
“It was remarkable that the compound rescued yeast cells and patient neurons in similar ways and through the same target—a target we would not have identified without yeast genetics to guide us,” says Khurana, a postdoctoral scientist in the Lindquist lab and a neurologist at Massachusetts General Hospital who recruited patients for participation in this research. Khurana believes that the abnormalities discovered occur in the early stages of disease. If so, successful manipulation of the targets identified here might help slow or even prevent disease progression.
For the researchers involved, these findings are a bit of surprise. Because neurodegenerative disorders like PD are largely diseases of aging, modeling them in a culture dish using neurons grown from iPS cells has been thought to be exceedingly difficult, if not impossible.
“Many, ourselves included, were skeptical that we could find any important pathologies for a neurodegenerative disorder by reprogramming patient cells,” says Chung, a Senior Research Scientist in the Lindquist lab. “Critically, we also validated these pathologies in post-mortem brains, so we’re quite confident these are relevant for the disease.”
Next steps for these scientists include chemically optimizing the compound identified and testing it in animal models. Moreover, they are convinced that this yeast-human stem cell discovery platform could be applied to other neurodegenerative diseases for which yeast models have been developed.
“Using yeast genetics to identify a compound and its mechanism of action against the fundamental pathology of a disease illustrates the power of the system we’ve built,” says Lindquist, who is also professor of biology at MIT and a Howard Hughes Medical Institute investigator. “It’s critical that we continue to leverage this power because as we reduce the rate at which people are dying from cancer and heart disease, the burden of these dreaded neurodegenerative diseases is going to rise. It’s inevitable.”
Shining light on neurodegenerative pathway
University of Adelaide researchers have identified a likely molecular pathway that causes a group of untreatable neurodegenerative diseases, including Huntington’s disease and Lou Gehrig’s disease.
The group of about 20 diseases, which show overlapping symptoms that typically include nerve cell death, share a similar genetic mutation mechanism ‒ but how this form of mutation causes these diseases has remained a mystery.
"Despite the genes for some of these diseases having been identified 20 years ago, we still haven’t understood the underlying mechanisms that lead to people developing clinical symptoms," says Professor Robert Richards, Head of Genetics in the University’s School of Molecular and Biomedical Sciences.
"By uncovering the molecular pathway for these diseases, we now expect to be able to define targets for intervention and so come up with potential therapies. Ultimately this will help sufferers to reduce the amount of nerve cell degeneration or slow its progression."
In an article published in Frontiers in Molecular Neuroscience, Professor Richards and colleagues describe their innovative theory and new evidence for the key role of RNA in the development of the diseases. RNA is a large molecule in the cell that copies genetic code from the cell’s DNA and translates it into the proteins that drive biological functions.
People with these diseases all have expanded numbers of copies of particular sequences of the ‘nucleotide bases’ which make up DNA.
"In most cases people with these diseases have increased numbers of repeat sequences in their RNA," says Professor Richards. "The disease develops when people have too many copies of the repeat sequence. Above a certain threshold, the more copies they have the earlier the disease develops and the more severe the symptoms. The current gap in knowledge is why having these expanded repeat sequences of genes in the RNA translates into actual symptoms."
Professor Richards says evidence points towards a dysfunctional RNA and a pivotal role of the body’s immune system in the development of the disease.
"Rather than recognising the ‘expanded repeat RNA’ as its own RNA, we believe the ‘expanded repeat RNA’ is being seen as foreign, like the RNA in a virus, and this activates the innate immune system, resulting in loss of function and ultimately the death of the cell," he says.
The University of Adelaide laboratory modelled and defined the expanded repeat RNA disease pathway using flies (Drosophila). Other laboratories have reported tell-tale, but previously inexplicable, signs characteristic of this pathway in studies of patients with Huntington’s disease and Myotonic Dystrophy.
"This new understanding, once proven in each of the relevant human diseases, opens the way for potential treatments, and should give cause for hope to those with these devastating diseases," Professor Richards says.
(Source: adelaide.edu.au)
Researchers Discover New Way to Track Huntington’s Disease Progression Using PET Scans
Investigators at The Feinstein Institute for Medical Research have discovered a new way to measure the progression of Huntington’s disease, using positron emission tomography (PET) to scan the brains of carriers of the gene. The findings are published in the September issue of The Journal of Clinical Investigation.
Huntington’s disease causes the progressive breakdown of nerve cells in the brain, which leads to impairments in movement, thinking and emotions. Most people with Huntington’s disease develop signs and symptoms in their 40s or 50s, but the onset of disease may be earlier or later in life. Medications are available to help manage the symptoms of Huntington’s disease, but treatments do not prevent the physical, mental and behavioral decline associated with the condition.
Huntington’s disease is an inherited disease, passed from parent to child through a mutation in the normal gene. Each child of a parent with Huntington’s disease has a 50/50 chance of inheriting the Huntington’s disease gene, and a child who inherits the gene will eventually develop the disease. Genetic testing for Huntington’s disease can be performed to determine whether a person carries the gene and is developing the disease even before symptoms appear. Having this ability provides an opportunity for scientists to study how the disease first develops and how it progresses in its early, presymptomatic stages. Even though a carrier of the Huntington’s disease gene may not have experienced symptoms, changes in the brain have already taken place, which ultimately lead to severe disability. Brain imaging is one tool that could be used to track how quickly Huntington’s disease progresses in gene carriers. Having a better way to track the disease at its earliest stages will make it easier to test drugs designed to delay or even prevent the onset of symptoms.
Researchers at the Feinstein Institute used PET scanning to map changes in brain metabolism in 12 people with the Huntington’s disease gene who had not developed clinical signs of the illness. The researchers scanned the subjects repeatedly over a seven-year period and found a characteristic set (network) of abnormalities in their brains. The network was used to measure the rate of disease progression in the study participants. The Feinstein Institute investigators then confirmed the progression rate through independent measurements in scans from a separate group of Huntington’s disease gene carriers who were studied in the Netherlands. The investigators believe that progression networks similar to the one identified in Huntington’s disease carriers will have an important role in evaluating new drugs for degenerative brain disorders.
“Huntington’s disease is an extremely debilitating disease. The findings make it possible to evaluate the effects of new drugs on disease progression before symptoms actually appear. This is a major advance in the field,” said David Eidelberg, MD, Susan and Leonard Feinstein Professor and head of the Center for Neurosciences at the Feinstein Institute.
(Source: northshorelij.com)
New clue on the origin of Huntington’s disease
The synapses in the brain act as key communication points between approximately one hundred billion neurons. They form a complex network connecting various centres in the brain through electrical impulses.
New research from Lund University suggests that it is precisely here, in the synapses, that Huntington’s disease might begin.
The researchers looked into the brains of mice with real-time imaging methods, following some of the very first stages of the disease through advanced microscopes. What they discovered was an unprecedented degradation of synaptic activity. Long before the well documented nerve cell death, synapses that are important for communication between brain centres that control memory and learning begin to wither. This process has never been mapped before and could be an important step towards understanding the serious non-motor symptoms that affect Huntington patients long before the movement disorders start to show.
“With the naked eye, we have now been able to follow the step by step events when these synapses start to break down. If we are to halt or reverse this process in the future, it is necessary to understand exactly what happens in the initial phase of the disease. Now we know more”, says Professor Jia-Yi Li, the research group leader.
Huntington’s disease has long been characterized by the involuntary writhing movements faced by patients. But in fact, Huntington’s has a very broad and highly individual symptomatology. Depression, memory loss and sleep disorders are all common early on in the disease.
“Many patients testify that these symptoms affect quality of life significantly more than the involuntary jerky movements. Therefore, it is extremely important that we achieve progress in this field of research. Our goal now is to find new therapies that can increase the lifespan of these synapses and maintain their vital function”, explains postdoc Reena, who lead the imaging experiments.
(Source: lunduniversity.lu.se)