Category: Huntington’s Disease

People who bear the genetic mutation for Huntington's disease learn faster than healthy people. The more pronounced the mutation was, the more quickly they learned. This is reported by researchers from the Ruhr-Universität Bochum and from Dortmund in the journal Current Biology.

The team has thus demonstrated for the first time that neurodegenerative diseases can go hand in hand with increased learning efficiency. "It is possible that the same mechanisms that lead to the degenerative changes in the central nervous system also cause the considerably better learning efficiency" says Dr. Christian Beste, head of the Emmy Noether Junior Research Group "Neuronal Mechanisms of Action Control" at the RUB.

Passive learning through repeated stimulus presentation

In a previous study, the Bochum psychologists reported that the human sense of vision can be changed in the long term by repeatedly exposing subjects to certain visual stimuli for short periods. The task of the participants was to detect changes in the brightness of stimuli. They performed better if they had viewed the stimuli passively for a while first. In the current study, the researchers presented the same task to 29 subjects with the genetic mutation for Huntington's disease, who, however, did not yet show any symptoms. They also tested 45 control subjects without such mutations in the genome. In both groups, the learning efficiency was better after passive stimulus presentation than without the passive training. Subjects with the Huntington's mutation, however, increased their performance twice as fast as those without the mutation.

Glutamate may have paradoxical effect

Degenerative diseases of the nervous system are based on complex changes. A key mechanism is an increased release of the neurotransmitter glutamate. However, since glutamate is also important for learning, in some cases it could lead to the paradoxical effect: better learning efficiency despite degeneration of the nerve cells.

Detecting differences in brightness under aggravated conditions

In each experimental run, the subjects saw two consecutive small bars on a computer screen that either had the same or different brightness. Sometimes, however, not only the brightness changed from bar one to bar two, but also the orientation of the bar (vertical or horizontal). "Normally, the distraction stimulus, i.e. the change in orientation, draws all the attention" Christian Beste explains. "But after the passive training with the visual stimuli, the distraction stimulus has no effect at all." The shift of attention from the non-relevant to the relevant properties of the stimulus was also visible in the electroencephalogram (EEG) in brain areas for early visual processing.

Better performance with stronger mutation

In Huntington's disease, a short segment of a gene is repeated. The number of repetitions determines when the disease breaks out. In the present study, a greater number of repetitions was, however, also associated with higher learning efficiency. "This shows that neurodegenerative changes can cause paradoxical effects" says Christian Beste. "The everyday view that neurodegenerative changes fundamentally entail deterioration of various functions can no longer be maintained in this dogmatic form."

Two new studies published in the inaugural issue of the Journal of Huntington's Disease hint at possible approaches to protect those at risk for HD.

In Huntington's disease, abnormally long strands of glutamine in the huntingtin (Htt) protein, called polyglutamines, cause subtle changes in cellular functions that lead to neurodegeneration and death. Studies have shown that the activation of the heat shock response, a cellular reaction to stress, doesn't work properly in Huntington's disease. In their research to understand the effects of mutant Htt on the master regulator of the heat shock response, HSF1, researchers have discovered that the targets most affected by stress are not the classic HSF1 targets, but are associated with a range of other important biological functions. Their research is published in the inaugural issue of The Journal of Huntington's Disease.

In the first genome-wide study of how polyglutamine (polyQ)-expanded Htt alters the activity of HSF1 under conditions of stress, the researchers found that under normal conditions, HSF1 function is very similar in cells carrying either wild-type (natural) or mutant Htt. Upon heat shock, much more dramatic differences emerge in the binding of HSF1. Unexpectedly, the genes no longer regulated by HSF1 were not classical HSF1 targets, such as molecular chaperones and the various genes involved in stress response. The genes that lost binding were associated with a range of other important biological functions, such as GTPase activity, cytoskeletal binding, and focal adhesion. Disorders in many of these functions have been linked to Huntington's disease in earlier studies; the current research provides a possible mechanism to explain previous observations.

Lead investigator Ernest Fraenkel, PhD, Associate Professor, Biological Engineering, MIT, explains that the impaired ability of HSF1 to respond to stress in these cells is consistent with the slow onset of Huntington's disease. Although polyQ-expanded Htt is expressed throughout the body, it primarily affects striatum and cortex relatively late in life. "An intriguing hypothesis is that polyQ-expanded Htt sensitizes the cells to various stresses, but is not sufficiently toxic on its own to cause cell death," he notes. "We have shown that polyQ Htt significantly blunts, but does not completely eliminate, the HSF1 mediated stress response. Over time, the reduced response may lead to significant damage and cell death."

The findings raise the possibility that activating HSF1 could be an effective strategy for protecting neurons from stress and damage. However, Dr. Fraenkel notes that such a strategy will have to overcome a number of barriers. "HSF1 is highly regulated, and simply increasing its expression may not increase the levels of the active form of HSF1. Also, increased HSF1 levels may raise the risk of cancer, as tumor cells depend on HSF1 activity. Further analysis of the role of HSF1 in neurodegeneration and cancer are critical to uncovering a safe and effective strategy for using HSF1 activation to treat Huntington's disease."

In another study published in the inaugural issue of the Journal of Huntington's Disease, investigators uncover a new biological marker that may be useful in screening antioxidative compounds for the treatment of Huntington's Disease. Serum 8OHdG is sign of oxidative damage to DNA, and has been shown to be elevated in patients with HD and other neurological disorders. Coenzyme Q (CoQ) is an antioxidant that may slow progression of Huntington's disease. It is also known to decrease 8OHdG levels in a mouse model of Huntington's disease. However, it was unknown whether CoQ dosing would reduce 8OHdG in humans.

Investigators administered CoQ to 14 Huntington's disease patients and 6 healthy controls for 20 weeks. Participants started on 1200 mg/day, and the dosage increased at week 8 to 3600 mg/day. CoQ levels were tested at the beginning of the study and at weeks 4, 8, 12, and 20. Four individuals with Huntington's disease reported that they were taking CoQ at the start of the study.

Baseline CoQ levels were elevated in individuals with Huntington's disease compared with health controls, even when individuals who were taking CoQ at the start of the study were excluded, the investigators found. The researchers suggest that individuals with Huntington's disease may have naturally high levels of CoQ, or some subjects may have recently discontinued CoQ, as CoQ levels can remain elevated in the system for several weeks.

Administration of CoQ led to a reduction of 8OHdG in individuals with Huntington's disease. While not significant, they found a similar reduction in healthy controls treated with CoQ, suggesting the effect of CoQ on 8OHdG may be non-specific.

"Our study supports the hypothesis that CoQ exerts antioxidant effects in patients with Huntington's disease and therefore is a treatment that warrants further study," says lead investigator Kevin M. Biglan, MD, MPH, Associate Professor, University of Rochester. "While the current data can't address the use of 8OHdG as a surrogate marker for the clinical effectiveness of antioxidants in Huntington's disease, we've established that 8OHdG can serve as a marker of the pharmacological activity of an intervention."

For the first time, scientists have linked a brain compound called kynurenic acid to cognition, possibly opening doors for new ways to enhance memory function and treat catastrophic brain diseases, according to a new study from the University of Maryland School of Medicine. When researchers decreased the levels of kynurenic acid in the brains of mice, their cognition was shown to improve markedly, according to the study, which was published in the July issue of the journal Neuropsychopharmacology. The study is the result of decades of pioneering research in the lab of Robert Schwarcz, Ph.D., a professor of psychiatry, pediatrics and pharmacology and experimental therapeutics at the University of Maryland School of Medicine.

"We believe that interventions aimed specifically at reducing the level of kynurenic acid in the brain are a promising strategy for cognitive improvement in both healthy patients and in those suffering from a variety of brain diseases ranging from schizophrenia to Alzheimer's disease," says Dr. Schwarcz.

Kynurenic acid is a substance with unique biological properties and is produced when the brain metabolizes the amino acid L-tryptophan. The compound is related to another breakdown product of tryptophan known as quinolinic acid. In 1983, Dr. Schwarz published a paper in the journal Science identifying the critical role excessive quinolinic acid plays in the neurodegenerative disorder Huntington's disease. He has since designed a therapeutic strategy targeting quinolinic acid for the treatment of Huntington's disease. Dr. Schwarcz also is involved in a company called VistaGen, which pursues the development of neuroprotective drugs based on this concept.

In the study published this month, Dr. Schwarcz and his colleagues at the Maryland Psychiatric Research Center — a clinical and basic science research center at the University of Maryland School of Medicine — examined mice that had been genetically engineered to have more than 70 percent lower kynurenic acid levels than ordinary mice. These mice were found to perform significantly better than their normal peers on several widely used tests that specifically measure function in the hippocampus. The hippocampus is a critical area of the brain for memory and spatial navigation. The mice were clearly superior in their ability to explore and recognize objects, to remember unpleasant experiences and to navigate a maze. The engineered animals also showed increased hippocampal plasticity, meaning they had a greatly improved ability to convert electrical stimuli into long-lasting memories.

"These results are very exciting, because they open up an entirely new way of thinking about the formation and retrieval of memories," says Dr. Schwarcz. "Kynurenic acid has been known for more than 150 years, but only now do we recognize it as a major player in one of the fundamental functions of the brain. Our most recent work, still unpublished, shows that new chemicals that specifically influence the production of kynurenic acid in the brain predictably affect cognition. We are now in the process of developing such compounds for cognitive enhancement in humans."

"I feel confident Dr. Schwarcz's determined pursuit of answers for the desperate patients suffering from devastating neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, and psychotic disorders such as schizophrenia, will pay off," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs, University of Maryland, and John Z. and Akiko K. Bowers Distinguished Professor and dean, University of Maryland School of Medicine. "His work creates hope for these patients and their families, and his findings are making a significant impact on the field of neuroscience and psychiatric medicine."

Medical researchers at the University of Alberta have discovered a promising new therapy for Huntington disease that restores lost motor skills and may delay or stop the progression of the disease, says researcher Simonetta Sipione.

The therapy is based on lab model tests and, because it uses a molecule already in clinical trials for other diseases, it could be used in a trial for Huntington disease within the next two years.

"We didn't expect to see such dramatic changes after administering this therapy," says Sipione, the principal investigator "We expected to see improvement, but not complete restoration of motor skills. When we saw this, we were jumping with excitement in the lab. This is very promising and should give hope to those with Huntington disease. It's a treatment that deserves to go to clinical trials because it could have huge potential."

People with this inherited brain disorder — characterized by a mutant protein that triggers brain cell death, loss of motor and cognitive skills and eventually death — have slightly lower levels of a brain molecule called GM1. When U of A medical researchers restored GM1 to normal levels in lab models with the disease, motor skills in the lab models returned to normal within days, says Sipione, a researcher in the Department of Pharmacology and the Centre for Neuroscience, both within the faculty of medicine and dentistry. Her team's research was recently published in the peer-reviewed journal Proceedings of the National Academy of Sciences.

The researchers used GM1 molecules in the lab tests that were both naturally and synthetically produced. This same molecule has been used in clinical trials for the treatment of Parkinson's and other neurodegenerative diseases, so a small first-stage clinical trial that uses GM1 for Huntington disease could happen relatively quickly.

Stakeholders are still working out where the trial would take place, but the research team involved is hoping it will be at the U of A and discussions are underway to secure the participation of a University of Alberta Hospital neurologist.

During the research stage, Sipione's team gave lab models the GM1 molecule therapy for four weeks. During the first two weeks after the treatment finished, the lab models still had normal motor function. But after that, motor function started to decline, returning to pre-treatment levels by the end of the fourth week; a potential treatment with this molecule would involve repeated applications over the long-term, says Sipione.

Sipione and her team are continuing to examine their research to see if restored levels of the GM1 molecule can also reverse cognitive damage in lab models with Huntington disease. They hope to publish the results from these tests within the year. Results indicate that GM1 therapy improves the way neurons work and makes the mutated Huntington protein less toxic.

"We think it will work on cognitive symptoms of the disease too," says Sipione, a Canada Research Chair Tier 2 in Neurobiology of Huntington disease and an Alberta Innovates Health Solutions Scholar. The Huntington Society of Canada funded the research and CEO Bev Heim-Myers says she is excited about the promising results.

"The Huntington Society of Canada is proud to support the excellent research of Dr. Sipione," Heim-Myers says. "Dr. Sipione, for the first time, has demonstrated that, in a Huntington disease laboratory model, the treatment reverts the lab model back to normal, not just slightly better.

"It is important to understand that some treatments may work in laboratory models but not in people. The applicability of the treatment discovered by Dr. Sipione to Huntington disease patients will be determined in clinical trials. We are optimistic that this research demonstrates real potential for a Huntington disease therapy."

A new study describes how hyperactivation of AMP-activated protein kinase (AMPK) promotes neurodegeneration in Huntington's disease (HD). The article appears online on July 18, 2011, in the Journal of Cell Biology.

The aggregation of mutant Huntingtin protein in HD disrupts many cellular processes, including metabolism. AMPK — a protein that balances a cell's energy production and usage — is abnormally active in the brains of mice with HD, but whether the kinase protects neurons from the metabolic imbalances associated with HD or whether AMPK contributes to neuronal death is unknown.

Yijuang Chern and colleagues determined that the alpha1 isoform of AMPK was specifically activated and translocated into the nuclei of neurons in a mouse model of HD, whereas AMPK-alpha2 was unaffected. An inhibitor of Ca2+/calmodulin-dependent protein kinase II reduced AMPK activity, suggesting that AMPK-alpha1 is activated by this kinase, probably because Ca2+ signaling is disrupted in HD neurons. Further stimulation of AMPK by injection of the AMPK-activating drug AICAR increased neuronal death and decreased the lifespan of HD mice. AICAR also promoted the death of neuronal cell lines, an effect reversed by an AMPK inhibitor. Active, nuclear AMPK-alpha1 promoted neuronal apoptosis by reducing expression of the cell survival factor Bcl2. Bcl2 levels and cell survival were restored by CGS21680, a drug that alleviates the symptoms of HD mice.

AMPK was also hyperactivated in the brains of human HD patients, suggesting that the kinase could be a therapeutic target. Chern now wants to investigate how AMPK-alpha1 and -alpha2 isoforms are differentially regulated in neuronal tissue.

Journal Reference:

1. Tz-Chuen Ju, Hui-Mei Chen, Jiun-Tsai Lin, Ching-Pang Chang, Wei-Cheng Chang, Jheng-Jie Kang, Cheng-Pu Sun, Mi-Hua Tao, Pang-Hsien Tu, Chen Chang, Dennis W. Dickson, and Yijuang Chern. Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease. Journal of Cell Biology, 2011 DOI: 10.1083/jcb.201105010

Medical researchers may have uncovered a novel approach to treat an incurable and ultimately fatal neurodegenerative disease that affects hundreds of thousands of people.

Two international studies, one led by the University of Leicester, and the other a collaboration with Leicester led by scientists in the USA, hold out promise for slowing down the development of Huntington's disease — and potentially, Alzheimer's and Parkinson's diseases. The research, which is in its early stages, represents an important milestone in understanding these debilitating conditions.

Huntington's disease is a devastating inherited neurodegenerative disorder that is always fatal. The disorder of the central nervous system causes progressive degeneration of cells in the brain, slowly impairing a person's ability to walk, think, talk and reason. Approximately 1 in 10,000 individuals are affected worldwide.

In the Department of Genetics at Leicester, the groups of Dr Flaviano Giorgini and Prof Charalambos Kyriacou found that by genetically targeting a particular enzyme in fruit-flies, kynurenine 3-monooxygenase or KMO, they arrested the development of the neurodegeneration associated with Huntington's disease. Furthermore by directly manipulating metabolites in the KMO cellular pathway with drugs, they could manipulate the symptoms that the flies displayed.

The fruit-fly study, to be published in Current Biology on June 7, was also aided by the groups of Prof Robert Schwarcz (Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore), who pioneered work in this area, and Dr Paul Muchowski (Gladstone Institutes, University of California, San Francisco). The two latter researchers and Dr Giorgini have simultaneously published a paper in Cell, announcing a similar breakthrough in understanding the therapeutic relevance of KMO in transgenic mouse models of Huntington's and Alzheimer's diseases. 

The fruit -fly research at Leicester took place over three years and was funded by the Huntington's Disease Association and the CHDI Foundation, Inc. Dr Giorgini, who led the UK study, states, "This work provides the first genetic and pharmacological evidence that inhibition of a particular enzyme — KMO — is protective in an animal model of this disease, and we have also found that targeting other points in this cellular pathway can improve Huntington's disease symptoms in fruit flies. This breakthrough is important as no drugs currently exist that halt progression or delay onset of Huntington's disease. We are tremendously excited about these studies, as we hope that they will have direct ramifications for Huntington's disease patients. Our work combined with the study in our companion publication in Cell, provides important confirmation of KMO inhibition as a potential therapeutic strategy for these individuals. As many KMO inhibitors are available, and more are being developed, it is hoped that such compounds can ultimately be tested in clinical trials for this as well as other neurodegenerative disorders."

In Leicester the experiments were carried out by Drs Susanna Campesan, Edward Green, and Carlo Breda and in Baltimore, by Dr Korrapati Sathyasaikumar. The collaborating teams will continue their studies aimed at enhancing the development of medical intervention in Huntington's and other neurodegenerative disorders.

Cath Stanley, Chief Executive of the Huntington's Disease Association, said: "This is an exciting piece of research that will offer hope to the many people affected by Huntington's disease."

Journal References:

1. Daniel Zwilling, Shao-Yi Huang, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W. Hsieh, Jamie Y. Louie, Tiffany Wu, Kimberly Scearce-Levie, Christina Patrick, Anthony Adame, Flaviano Giorgini, Saliha Moussaoui, Grit Laue, Arash Rassoulpour, Gunnar Flik, Yadong Huang, Joseph M. Muchowski, Eliezer Masliah, Robert Schwarcz, Paul J. Muchowski. Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration. Cell, 2011; DOI: 10.1016/j.cell.2011.05.020
2. Susanna Campesan, Edward W. Green, Carlo Breda, Korrapati V. Sathyasaikumar, Paul J. Muchowski, Robert Schwarcz, Charalambos P. Kyriacou, Flaviano Giorgini. The Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington's Disease. Current Biology, 2011; 21 (11): 961-966 DOI: 10.1016/j.cub.2011.04.028

Researchers at the Department of Energy's Oak Ridge National Laboratory and the University of Tennessee have for the first time successfully characterized the earliest structural formation of the disease type of the protein that causes Huntington's disease. The incurable, hereditary neurological disorder is always fatal and affects one in 10,000 Americans.

Huntington's disease is caused by a renegade protein "huntingtin" that destroys neurons in areas of the brain concerned with the emotions, intellect and movement. All humans have the normal huntingtin protein, which is known to be essential to human life, although its true biological functions remain unclear.

Christopher Stanley, a Shull Fellow in the Neutron Scattering Science Division at ORNL, and Valerie Berthelier, a UT Graduate School of Medicine researcher who studies protein folding and misfolding in Huntington's, have used a small-angle neutron scattering instrument, called Bio-SANS, at ORNL's High Flux Isotope Reactor to explore the earliest aggregate species of the protein that are believed to be the most toxic.

Stanley and Berthelier, in research published in Biophysical Journal, were able to determine the size and mass of the mutant protein structures―from the earliest small, spherical precursor species composed of two (dimers) and three (trimers) peptides―along the aggregation pathway to the development of the resulting, later-stage fibrils. They were also able to see inside the later-stage fibrils and determine their internal structure, which provides additional insight into how the peptides aggregate.

"Bio-SANS is a great instrument for taking time-resolved snapshots. You can look at how this stuff changes as a function of time and be able to catch the structures at the earliest of times," Stanley said. "When you study several of these types of systems with different glutamines or different conditions, you begin to learn more and more about the nature of these aggregates and how they begin forming."

Normal huntingtin contains a region of 10 to 20 glutamine amino acids in succession. However, the DNA of Huntington's disease patients encodes for 37 or more glutamines, causing instability in huntingtin fragments that contain this abnormally long glutamine repeat. Consequentially, the mutant protein fragment cannot be degraded normally and instead forms deposits of fibrils in neurons.

Those deposits, or clumps, were originally seen as the cause of the devastation that ensues in the brain. More recently researchers think the clumping may actually be a kind of biological housecleaning, an attempt by the brain cells to clean out these toxic proteins from places where they are destructive. Stanley and Berthelier set out to learn through neutron scattering what the toxic proteins were and when and where they occurred.

At the HFIR Bio-SANS instrument, the neutron beam comes through a series of mirrors that focus it on the sample. The neutrons interact with the sample, providing data on its atomic structure, and then the neutrons scatter, to be picked up by a detector. From the data the detector sends of the scattering pattern, researchers can deduce at a scale of less than billionths of a meter the size and shape of the diseased, aggregating protein, at each time-step along its growth pathway.

SANS was able to distinguish the small peptide aggregates in the sample solution from the rapidly forming and growing larger aggregates that are simultaneously present. In separate experiments, they were able to monitor the disappearance of the single peptides, as well as the formation of the mature fibrils.

Now that they know the structures, the hope is to develop drugs that can counteract the toxic properties in the early stages, or dissuade them from taking the path to toxicity. "The next step would be, let's take drug molecules and see how they can interact and affect these structures," Stanley said.

For now, the researchers believes Bio-SANS will be useful in the further study of Huntington's disease aggregates and applicable for the study of other protein aggregation processes, such as those involved in Alzheimer's and Parkinson's diseases.

"That is the future hope. Right now, we feel like we are making a positive contribution towards that goal," Stanley said.

The research was supported by the National Institutes of Health. HFIR and Bio-SANS are supported by the DOE Office of Science.

Journal Reference:

1. Christopher B. Stanley, Tatiana Perevozchikova, Valerie Berthelier. Structural Formation of Huntingtin Exon 1 Aggregates Probed by Small-Angle Neutron Scattering. Biophysical Journal, 2011; 100 (10): 2504-2512 DOI: 10.1016/j.bpj.2011.04.022

NewsPsychology (May 12, 2011) — New research sheds light on common pathogenic mechanisms shared by Huntington’s disease (HD) and HD-like disorders. The study, published by Cell Press in the May 12, 2011, issue of the journal Neuron, uses a new transgenic mouse model for an HD-like disorder to unravel complex molecular events that drive disease pathology.

Huntington’s disease like-2 (HDL2) is a rare neurodegenerative disorder that is similar to HD. However, HDL2 patients do not have the HD-causing mutation: a repeating CAG sequence in the huntingtin gene that codes for the amino acid glutamine. This mutation results in the production of a chain of glutamines called a polyglutamine (or polyQ) tract within the mutant huntingtin protein. Instead, HDL2 is caused by a CTG/CAG repeat within a region of the Junctophilin-3 (JPH3) gene.

“Both HD and HDL2 brains contain a pathological hallmark called ‘intranuclear inclusions’ (NIs) that have a similar but not identical distribution pattern in the brain,” says senior study author, Dr. X. William Yang, from the Semel Institute at the University of California, Los Angeles. “The NIs in HD contain mutant huntingtin protein, but those in HDL2 do not. Therefore, the pathogenic origins of NIs in HDL2 and the mechanisms underlying HDL2 pathogenesis remain to be uncovered.”

To gain new insight into HDL2, Dr. Yang and colleagues at UCLA, and collaborators led by Dr. Russell Margolis at Johns Hopkins University, developed a series of bacterial artificial chromosome (BAC)-mediated transgenic mouse models of HDL2 (BAC-HDL2) that contain an expanded CTG/CAG repeat in the human JPH3 gene, as well as control BAC mice with a nonexpanded CTG/CAG repeat. BACs have been shown to be useful for modeling genetic diseases because they allow introduction of a large piece of human DNA carrying the disease mutation into the mouse genome, thereby permitting the accurate expression of the disease gene similar to that in the patient.

The researchers found that the BAC-HDL2 mice exhibited several key characteristics found in HDL2 patients, including age-dependent motor deficits, selective forebrain atrophy, and brain region-specific distribution of NIs. Molecular analysis revealed that a novel promoter was driving expression of an unexpected section of DNA which encoded a polyQ protein. Importantly, BAC-HDL2, but not control BAC mice, accumulated polyQ-containing NIs in a pattern that was remarkably similar to that seen in HDL2 patients.

The findings point to overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2. “We have generated and characterized the first BAC transgenic mouse models of an HD-like disorder, HDL2,” concludes Dr. Yang. “Our analysis suggests that expression of a novel expanded polyQ protein could play a critical role in HDL2 pathogenesis and provides experimental evidence to suggest that HD and HDL2 may have overlapping polyQ-mediated disease mechanisms. Further elucidation of such mechanisms may provide therapeutic targets for both disorders.”

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The above story is reprinted (with editorial adaptations by newsPsychology staff) from materials provided by Cell Press, via EurekAlert!, a service of AAAS.

Journal Reference:

1. Brian Wilburn, Dobrila D. Rudnicki, Jing Zhao, Tara Murphy Weitz, Yin Cheng, Xiaofeng Gu, Erin Greiner, Chang Sin Park, Nan Wang, Bryce L. Sopher, Albert R. La Spada, Alex Osmand, Russell L. Margolis, Yi E. Sun, X. William Yang. An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington’s Disease-like 2 Mice. Neuron, 2011; 70 (3): 427-440 DOI: 10.1016/j.neuron.2011.03.021

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of NewsPsychology or its staff.

For years, researchers in genome stability have observed that several neurodegenerative diseases — including Huntington's disease — are associated with cell-killing proteins that are created during expansion of a CAG/CTG trinucleotide repeat.

In research published in the March 17 online edition of the journal PLoS Genetics, Tufts University biologist Catherine Freudenreich, and then-graduate student Rangapriya Sundararajan show that cell death in yeast can also result from the process by which the cell repairs damage that occurs within a repeated CAG/CTG sequence.

The findings provide additional insight into the causes of some neurodegenerative diseases. "This represents a new way in which the expanded repeats may be causing cell death that leads to the disease," says Freudenreich. , associate professor of biology at the School of Arts and Sciences at Tufts University "The expanded DNA in and of itself can be toxic to cells."

Scientists have observed that Huntington's disease, myotonic dystrophy and multiple subtypes of spinal cerebella ataxia are caused when the number of repeats at the disease locus exceeds a stability threshold.

For Huntington's disease, the threshold is 38 to 40 repeats. Myotonic dystrophy results when there are close to 200 repeats.

When these expanded repeats occur, the abnormal DNA is copied faithfully into ribonucleic acid, the chemical cousin of DNA. In myotonic dystrophy the errant RNA has a toxic effect because it grabs onto and holds hostage certain proteins, preventing them from carrying out the myriad functions that are vital to the cell.

In Huntington's disease and the ataxias, the RNA serves as a blueprint for an abnormal protein that contains an excessive amount of an amino acid called glutamine.

In her experiment, Freudenreich found a cause of cell death that arises from a DNA checkpoint response.

She started with a piece of human DNA that was cloned from a myotonic dystrophy patient. It contained CAG/CTG repeats of 70 and 155. She then placed the tract within a yeast chromosome.

Multiple types of DNA damage can occur at an expanded trinucleotide repeat. Damage of this magnitude triggers checkpoint proteins that respond like genomic firefighters to the emergency.

In normal circumstances these proteins halt the cell growth cycle until the damage is repaired.

In Freudenreich's study, the cell damage activated the Rad53 checkpoint kinase. But here, the protein arrested cell growth for an abnormally long period of time without repairing the damage. This often resulted in cell death.

In cases where the cell did manage to recover and keep dividing, the researchers observed an increased frequency of repeat expansions. "The cells that were having trouble growing and dividing due to the expanded repeat accumulated additional expansions. It became a vicious loop," says Freudenreich. She adds, "It will be important in the future to determine if this phenomenon is contributing to the cell death that causes the human diseases."

Myotonic dystrophy is an inherited condition that affects muscles and other body systems. It is the most common form of adult onset muscular dystrophy, with progressive muscle wasting as well as a variety of other symptoms.

Huntington's disease is a genetic disease involving degeneration of the central nervous system, leading to uncontrolled muscle movements, emotional instability and dementia. Folk musician and songwriter Woody Guthrie died from complications of the disease in 1967.

Freudenreich and Sundararajan's work was funded by a National Institutes of Health grant.

Journal Reference:

1. Rangapriya Sundararajan, Catherine H. Freudenreich. Expanded CAG/CTG Repeat DNA Induces a Checkpoint Response That Impacts Cell Proliferation in Saccharomyces cerevisiae. PLoS Genetics, 2011; 7 (3): e1001339 DOI: 10.1371/journal.pgen.1001339