Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSF transgenic mouse mimics Parkinson’s earliest symptoms

04.05.2010
UCSF researchers have created the first transgenic mouse to display the earliest signs of Parkinson’s disease using the genetic mutation that is known to accompany human forms of the disease.

The mouse model, which expresses the same mutant proteins as human Parkinson’s patients, also displays early signs of constipation and other gastrointestinal problems that are a common harbinger of the disease in humans.

As a result, researchers say, these animals could serve as a means of investigating therapies for reversing the neurological dysfunction of the disease at its earliest stages.

The findings are featured as the cover story in the May 1, 2010 issue of the journal, “Human Molecular Genetics” and are available online at http://hmg.oxfordjournals.org/cgi/content/full/19/9/1633.

Researchers have long suspected that the neurological component of Parkinson’s, which causes tremors and stiffness among other symptoms, is actually a late-stage effect of a larger, systemic problem, according to UCSF geneticist Robert L. Nussbaum, MD, who was senior author on the paper.

“This new model validates that theory by mimicking what we know to be the genetic pathway leading to Parkinson’s, while also displaying the earliest symptoms that occur in humans,” said Nussbaum, who is the Holly Smith Distinguished Professor in Medicine and chief of the UCSF Division of Medical Genetics. “This will give us an important tool in identifying an early intervention for this devastating disease.”

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s, affecting 1.5 percent of adults over 55 years of age, and is typically characterized by motor disorders such as tremors, rigidity and postural instability.

Several non-motor abnormalities also frequently accompany Parkinson’s, including depression, sleep disorders and gastrointestinal dysfunction, the researchers explained. Gastrointestinal dysfunction is a particularly common symptom, seen in 80 to 90 percent of patients, and often precedes the motor-control symptoms by 10 to 15 years.

The UCSF mouse model is the first to display the full gastrointestinal symptoms as well, and is consistent with the progression of the disease in humans.

Nussbaum, in collaboration with former colleague Mihael Polymeropoulos, MD, had previously identified the first Mendelian-inherited form of Parkinson’s, which involves a mutation in the gene that produces alpha-synuclein proteins. Since then, he has been studying the rare, inherited forms of the disease to better understand the pathways and processes that may be involved in the more common, sporadic forms, and to create mouse models of the disease that can help in developing therapies.

The current model, based on that research, is significant in having the same genetic mutation that causes alpha-synuclein to misfold in an inherited form of Parkinson’s, causing the proteins to stick together to form insoluble fibrils in the nerve cells. Those clumps, known as Lewy bodies, are often associated with Parkinson’s, as well as with some other forms of dementia and multiple system atrophy.

Previous mouse models of the disease had relied on an over-expression of alpha-synuclein caused by a combination of human and mouse genes, according to the paper. The UCSF team created two new lines that only express the human form of the protein, with each line expressing one of two mutant forms that occur in human Parkinson’s patients, according to lead author Yien-Ming Kuo, PhD, in the UCSF Institute for Human Genetics.

In these lines, gastrointestinal dysfunction could be seen at three months of age, reached its highest severity at six months and persisted until 18 months, which follows the human course of the disease in sporadic Parkinson’s, according to the paper. That dysfunction occurred before there was any evidence of loss of smell and also before any evidence arose of pathological changes in the brain stem.

“This suggests that, at least in mice with the human proteins, these gastrointestinal symptoms are an intrinsic defect caused by the mutant protein, rather than being caused by abnormalities in brain function,” Kuo said. “That knowledge could eventually help us test for the disease long before it starts to cause neurodegenerative problems and prevent them from occurring.”

The work was funded by the National Institutes of Health, a grant from the Michael J. Fox Foundation, institutional funding from the UCSF Department of Medicine and Institute of Human Genetics, and the American Lebanese Syrian Associated Charities. The authors report no conflicts of interest on this research.

Co-authors on the paper include Zhishan Li and Michael D. Gershon, from the Department of Pathology and Cell Biology, Columbia University, New York, NY; Yun Jiao, Amar K. Pani and Richard J. Smeyne, of the Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN; Nathalie Gaborit and Benoit G. Bruneau, of the Gladstone Institute of Cardiovascular Disease, San Francisco, CA; Bonnie M. Orrison of the Genetic Disease Research Branch, National Institutes of Health, Bethesda, MD; and Benoit I. Giasson, of the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, visit ucsf.edu.

Kristen Bole | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>