The song of the canary aids the quest to create medium spiny neurons
Paying close attention to how a canary learns a new song has helped scientists open a new avenue of research against Huntington’s disease – a fatal disorder for which there is currently no cure or even a treatment to slow the disease.
In a paper published Sept. 20 in the Journal of Clinical Investigation, scientists at the University of Rochester Medical Center have shown how stem-cell therapy might someday be used to treat the disease. The team used gene therapy to guide the development of endogenous stem cells in the brains of mice affected by a form of Huntington’s. The mice that were treated lived significantly longer, were healthier, and had many more new, viable brain cells than their counterparts that did not receive the treatment.
While it’s too early to predict whether such a treatment might work in people, it does offer a new approach in the fight against Huntington’s, says neurologist Steven Goldman, M.D., Ph.D., the lead author of the study. The defective gene that causes the disease has been known for more than a decade, but that knowledge hasn’t yet translated to better care for patients.
“There isn’t much out there right now for patients who suffer from this utterly devastating disease,” said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. “While the promise of stem cells is broadly discussed for many diseases, it’s actually conditions like Huntington’s – where a very specific type of brain cell in a particular region of the brain is vulnerable – that are most likely to benefit from stem-cell-based therapy.”
The lead authors of the latest paper are Abdellatif Benraiss, Ph.D., research assistant professor at the University, and former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea.
The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. In basic neuroscience studies, Goldman was investigating how canaries learn new songs, and he found that every time a canary learns a new song, it creates new brain cells called neurons. His doctoral thesis in 1983 was the first report of neurogenesis – the production of new brain cells – in the adult brain, and opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells.
The finding led to a career for Goldman, who has created ways to isolate stem cells. These techniques have allowed Goldman’s group to discover the molecular signals that help determine what specific types of cells they become, and re-create those signals to direct the cells’ development. Benraiss has worked closely with Goldman for more than 10 years on the Huntington’s project.
“The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington’s disease,” said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. “Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington’s disease.”
Huntington’s is an inherited disorder that affects about 30,000 people in the U.S. A defective gene results in the death of vital brain cells known as medium spiny neurons, resulting in involuntary movements, problems with coordination, cognitive difficulties, and depression and irritability. The disease usually strikes in young to mid adulthood, in a patient’s 30s or 40s; there is currently no way to slow the progression of the disease, which is fatal.
Stem cells offer a potential pool to replace neurons lost in almost any disease, but first scientists must learn the extensive molecular signaling that shapes their development. The fate of a stem cell depends on scores of biochemical signals – in the brain, a stem cell might become a dopamine-producing neuron, perhaps, or maybe a medium spiny neuron, cells that are destroyed by Parkinson’s and Huntington’s diseases, respectively.
To do this work, Goldman’s team set up a one-two molecular punch as a recipe for generating new medium spiny neurons, to replace those that had become defective in mice with the disease. The team used a cold virus known as adenovirus to carry extra copies of two genes into a region of the mouse brain, called the ventricular wall, that is home to stem cells. This area happens to be very close to the area of the brain, known as the neostriatum, which is affected by Huntington’s disease.
The team put in extra copies of a gene called Noggin, which helps stop stem cells from becoming another type of cell in the brain, an astrocyte. They also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor), which helps stem cells become neurons. Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.
The results in mice, which had a severe form of Huntington’s disease, were dramatic. The mice had several thousand newly formed medium spiny neurons in the neostriatum, compared to no new neurons in mice that weren’t treated, and the new neurons formed connections like medium spiny neurons normally do. The mice lived about 17 percent longer and were healthier, more active and more coordinated significantly longer than the untreated mice.
The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Now that the capability has been demonstrated, Goldman is working on ways to extend the duration of the improvement. Ultimately he hopes to assess this potential approach to treatment in patients.
“This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development,” said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington’s Disease Center of Excellence and is the base for the Huntington Study Group.
In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children’s Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.
Contact: Tom Rickey
University of Rochester Medical Center
McMaster University researchers have first insight into how Huntington’s disease is triggered
McMaster University researchers have first insight into how Huntington’s disease (HD) is triggered. The research will be published online in the British Journal, Human Molecular Genetics, on Monday, August 20.
“These are exciting results by the McMaster team,” said Dr. Rémi Quirion, Scientific Director at the Canadian Institutes of Health Research, Institute of Neuroscience, Mental Health and Addiction. Even if the huntingtin protein has been known for almost 20 years, the cause of Huntington’s disease is still not clear. Data reported here shed new lights on this aspect and possibly leading to new therapeutic potential in the future.”
Ray Truant, professor in the Department of Biochemistry and Biomedical Sciences, has been studying the biological role of the huntingtin protein and the sequences in the protein that tell it where to go within a brain cell.
Huntington disease (HD) is a neurological disorder resulting from degeneration of brain cells. The degeneration causes uncontrolled limb movements and loss of intellectual faculties, eventually leading to death. There is no treatment. HD is a familial disease, passed from parent to child through a mutation in the normal gene. The disorder is estimated to affect about one in every 10,000 persons.
Truant and PhD candidate graduate student, Randy Singh Atwal, have discovered a small protein sequence in huntingtin that allows it to locate to the part of the cell critical for protein quality control. Similar findings have been seen to be very important for other neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.
Huntingtin protein is essential for normal development in all mammals, and is found in all cells, yet its function was unknown. It appears that huntingtin is crucial for a brain cell’s response to stress, and moves from the endoplasmic reticulum into the nucleus, the control centre of the cell. When mutant huntingtin is expressed however, it enters the nucleus as it should in response to stress, but it cannot exit properly, piling up in the nucleus and leading to brain cell death in HD.
“What is important to Huntington disease research is that in the learning of the basic cell biology of this protein, we have also uncovered a new drug target for the disease,” says Atwal.
Atwal additionally found that huntingtin can be sent to the nucleus by protein modifying enzymes called kinases, and he has determined the three-dimensional shape of this sequence.
Truant and Atwal’s work indicates that if mutant huntingtin is prevented from entering the nucleus, it cannot kill a brain cell. This means that a kinase inhibitor drug may be effective for Huntington’s disease. Kinase inhibitors form the largest number of successful new generation drugs that are coming to market for a plethora of diseases including stroke, arthritis and cancer.
“This is most exciting to us, because we immediately have all the tools and support in hand at McMaster to quickly hunt this kinase down, and find potential new drugs for Huntington’s disease in ways that are similar or better than a large pharmaceutical company”, says Truant. Truant’s lab is also collaborating in the US with the Cure Huntington’s Disease Initiative (CHDI) a novel, non-profit virtual pharmaceutical company focused on HD.
A large portion of this work was completed in the new McMaster biophotonics facility (www.macbiophotonics.ca), and additional research will be done in McMaster’s unique high throughput screening lab (hts.mcmaster.ca) and other new labs being established at the University.
“We can actually watch huntingtin protein move inside of a single live brain cell in real time in response to stress, and we can watch mutant huntingtin kill that cell, even over days,” says Truant. “Using molecular tools, computer software and sophisticated laser microscopy techniques which we’ve been developing at McMaster over the last seven years, researchers can now use these methods to hopefully watch a drug stop this from happening.”
Truant’s laboratory is supported by grants from the United States High Q Foundation, the Canadian Institutes of Health Research, the Huntington Society of Canada and the Canada Foundation for Innovation.
“This discovery reflects Dr. Truant’s growing contribution to the international campaign to create a world free from Huntington disease,” says Don Lamont, CEO & Executive Director of the Huntington Society of Canada – Canada’s only organization focused on research, education and support in the HD field.
“Our families live on a ‘tightrope’ waiting for an effective treatment or a cure for HD”, says Lamont. “The discovery provides hope for the Huntington community – most of all, hope that their children will not have to suffer the devastation of this inherited disease.”
Contact: Veronica McGuire
Contact: Kris Rebillot
Buck Institute for Age Research
Buck Institute faculty leads large scale screening of protein interactions to identify drug targets for possible treatment of incurable disease
Researchers from four organizations have identified more than 200 new proteins that bind to normal and mutant forms of the protein that causes Huntington’s disease (HD). HD is a fatal inherited disease that affects 30,000 Americans annually by laying waste to their nervous system. The research was led by Buck Institute faculty member Robert E. Hughes, PhD. Results of the study, which may facilitate the discovery of an effective treatment for HD, will be published in the May 11 edition of PLoS Genetics, an online, open-source journal, enabling scientists from around the world to take advantage of the findings immediately.
The work, which involved high-tech screening of the human genome and proteome, was unprecedented both in terms of its scale and in the way the protein interactions were validated in a genetic model of the disease. By conducting additional experiments in fruit flies genetically altered to express features of human HD, scientists showed that changing the expression of these interacting proteins affected the degree of damage seen in the fly neurons. This indicates that a significant number of the proteins might be potential drug targets for HD.
Now that researchers have discovered the interacting proteins using human libraries and human protein extracts and tested them in the fly, Hughes says the next step is to bring the research back into the mammalian world. The new genes and proteins discovered in this study are being screened and analyzed in cultured mammalian cells; the ones that show activity in ongoing experiments will be tested in mouse models of HD.
“Here at the Buck Institute, we’re going to be focusing on a few dozen proteins,” said Hughes. “Effective follow-up on any target protein depends, in large part, on how much expertise a scientist has with that target. We are hoping that researchers will look at this study and that those with specific expertise in a particular protein will move forward with their own inquiries.”
The work was supported by HD advocacy organizations. “We are very excited about this significant discovery,” said Allan Tobin, PhD, Senior Scientific Advisor to the High Q Foundation and CHDI, Inc. “This work helps define and refine possible therapeutic targets for a disease that lacks thorough understanding.” Tobin added, “We are pleased this study is being published in an open-access journal, which makes it easier for scientists at other organizations to get to work on following up on this landmark discovery.” Traditional peer-reviewed journals usually require scientists to pay a fee to access study results.
Tobin added that the need for further scientific inquiry is urgent. There is currently no effective treatment or cure for HD, which is typically characterized by involuntary movements and dementia. The disease slowly diminishes a person’s ability to move, think and communicate. Those affected eventually become totally dependent on others for their care and usually die from complications such as choking, heart failure or infection. The disease is hereditary; each child of a person with HD has a 50/50 chance of inheriting the fatal gene. Approximately 200,000 Americans are believed to be at risk of developing HD, a disease that affects as many people as hemophilia, cystic fibrosis or muscular dystrophy. The symptoms of HD typically begin to appear in mid-life, although the progression of the disease varies among individuals and within the same family.
Joining Hughes as co-authors of the paper are Buck Institute scientists Cameron Torcassi, and Lisa Ellerby; along with Eliana Romano and Juan Botas from the Baylor College of Medicine in Houston; Andrew Strand, and James Olson from the Fred Hutchinson Cancer Research Center in Seattle; and Linda Kaltenbach, Sudhir Sahasrabudhe, Cornelia Kurschner, and John M. Peltier of Prolexys Pharmaceuticals in Salt Lake City. The work was supported by grants from the HighQ Foundation, CCHI Inc, the Hereditary Disease Foundation and National Institutes of Health.
The Buck Institute is an independent non-profit organization dedicated to extending the healthspan, the healthy years of each individual’s life. The National Institute of Aging designated the Buck a Nathan Shock Center of Excellence in the Biology of Aging, one of just five centers in the country. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer’s and Parkinson’s disease, cancer, stroke, and arthritis. Collaborative research at the Institute is supported by genomics, proteomics and bioinformatics technology. For more information: http://www.buckinstitute.org.
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