Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Brain protein central to both Parkinson's, drug addiction identified

07.05.2009
Astrocytes come under scrutiny for yet another neurodegenerative disorder

Scientists have identified a protein that appears not only to be central to the process that causes Parkinson's disease but could also play a role in muting the high from methamphetamine and other addictive drugs.

The action of the protein, known as organic cation transporter 3 or oct3, fills a longstanding gap in scientists' understanding of the brain damage that causes symptoms like tremor, stiffness, slowness of movement and postural instability. While these are found mainly in patients with Parkinson's disease, there are more than three dozen other known causes of this array of symptoms, known as "parkinsonism."

In a paper published online this week in the Proceedings of the National Academy of Sciences, scientists at Columbia University Medical Center and the University of Rochester Medical Center have shown that oct3, a protein that shepherds molecules into and out of cells, plays a critical role, bringing toxic chemicals to the doorstep of the brain cells that die in patients with Parkinson's disease. The team found that oct3 is involved in the brain's response to addictive drugs like methamphetamine as well.

Precisely what causes Parkinson's disease remains largely a mystery. Some cases have a known genetic basis, and most others are attributed to environmental causes or a combination of gene-environment interactions. Doctors know that symptoms of Parkinson's stem from the death of a very small, specialized group of brain cells known as dopamine neurons, which produce a chemical needed by another area of the brain to help us move freely. It's not until most of those brain cells have already died that patients begin to show symptoms.

For decades, scientists have been trying to understand why those cells die. The latest paper supports a role for astrocytes, a type of cell that is the most common in the brain but which has been often overlooked by scientists focused more on cells known as neurons that send electrical signals. Astrocytes' role in Parkinson's is no surprise to brain experts who have also identified them as a player in Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy, and other diseases.

"Astrocytes are definitely much more than support cells in the brain," said Kim Tieu, Ph.D., a corresponding author of the paper and assistant professor in the Department of Environmental Medicine at the University of Rochester Medical Center. "Scientists are discovering their involvement in many diseases. The latest results point to their role in Parkinson's disease."

Tieu initiated the study while a post-doctoral research associate in the laboratory of Serge Przedborski, M.D., Ph.D., the Page and William Black Professor of Neurology at Columbia University and a corresponding author. They chose to study how the brain handles a chemical known as MPTP, which ultimately damages the exact same brain cells that are injured in patients with Parkinson's disease. While MPTP does not cause Parkinson's disease, scientists regularly use it as a model for the disease because it causes an identical type of brain damage.

In the brain, MPTP is converted primarily in astrocytes to a chemical called MPP+, which is deadly to dopamine neurons. More than 20 years ago, as a graduate student with Solomon Snyder, M.D., Jonathan Javitch, M.D., Ph.D., now professor of psychiatry and pharmacology at Columbia and an author on the current paper, concluded that MPP+ is released from astrocytes before it kills dopaminergic neurons. But exactly how MPP+ is freed from astrocytes was unknown.

In this week's PNAS paper, the scientists finger oct3 as the shepherd that escorts toxic MPP+ out of the astrocytes and into the space surrounding dopamine neurons. That's where another molecule known as the dopamine transporter picks it up and brings it into the neuron itself.

When the team blocked or genetically removed oct3 in mice, the dopamine neurons in the brains did not die despite the presence of MPTP in the brain. Without oct3, MPP+ remained sequestered inside astrocytes and did not affect the dopamine neurons. And when oct3 was present in the usual amounts, dopamine neurons died as expected.

"The neurons affected in Parkinson's disease don't live in isolation in the brain," said Przedborski. "You must understand the brain environment as a whole to understand disease. For many years, people had a neuron-centric view of neurodegenerative diseases. But more and more scientists are realizing that if you wish to understand the process of neurodegeneration, you must take into account the astrocytes, the microglia, as well as the neurons. Astrocytes maintain an intimate relationship with neurons, and to understand one, you have to understand the other."

The team also analyzed brain tissue from people who died of Parkinson's disease and found that oct3 is active in astrocytes in the brain region affected by Parkinson's disease. They found the same thing in mice, where the absence of oct3 correlated exactly to areas of the brain where neurons were not damaged.

The team also showed that oct3 plays a role in the brain's response to methamphetamine. Oct3 is critical for helping astrocytes soak up excess dopamine in the space around neurons. When dopamine isn't removed as quickly or thoroughly as usual, people can feel euphoric, but they can also experience brain damage. The finding that oct3 may play a role matches other scientists' observations that people in whom oct3 activity is reduced have a higher potential for addiction.

The molecule might also offer a new target for treating depression. Many anti-depressants work by allowing the brain chemical serotonin to stay available in the brain longer than it otherwise would. Since one of oct3's functions is to remove serotonin from the brain, blocking it may offer a new avenue to treat depression.

The chemicals that the team used to block oct3 in mice would be toxic in people, and there is no drug available for people now that blocks or boosts oct3, Tieu and Przedborski said. But such a drug might be useful for Parkinson's, drug addiction, and depression.

"How you choose to manipulate the function of oct3 depends on the source of the toxic molecules," said Tieu, who is also a scientist in the University's Center for Neural Development and Disease. "You would try to lessen its effects in a condition where it makes a toxic molecule available to vulnerable cells, as illustrated in the current model of Parkinson's disease. But in the case of drug addiction, you might try to increase it, to lessen the impact of a drug like methamphetamine."

Other authors at the University of Rochester include post-doctoral research associates Mei Cui, Ph.D., Radha Aras, Ph.D., and Mamata Hatwar, Ph.D.; graduate student Whitney Christian; medical and graduate student Phillip Rappold; former undergraduate student Joseph Panza; and Ned Ballatori, Ph.D., professor of environmental medicine. At Columbia, Vernice Jackson-Lewis, Ph.D., associate research scientist, also contributed to the research. The work was funded by the National Institute of Environmental Health Sciences.

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the most comprehensive medical research enterprise in New York City and state and one of the largest in the United States. Columbia University Medical Center is affiliated with NewYork-Presbyterian Hospital, the nation's largest not-for-profit hospital provider.

Karin Eskenazi | EurekAlert!
Further information:
http://www.columbia.edu
http://www.cumc.columbia.edu

More articles from Life Sciences:

nachricht Designer cells: artificial enzyme can activate a gene switch
22.05.2018 | Universität Basel

nachricht Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Spinning rugby balls: The rotation of the most massive galaxies

23.05.2018 | Physics and Astronomy

Raiding the rape field

23.05.2018 | Agricultural and Forestry Science

Turning entanglement upside down

23.05.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>