Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

‘Deranged Calcium Signaling’ Contributes to Neurological Disorder

27.11.2008
Defective calcium metabolism in nerve cells may play a major role in a fatal genetic neurological disorder that resembles Huntington’s disease, researchers at UT Southwestern Medical Center have found in a mouse study.

The disease, called spinocerebellar ataxia 3 – also known as SCA3, or Machado-Joseph disease – is a genetic disorder that, like Huntington’s, impairs coordination, speech, and vision and causes brain atrophy. Although rare, the condition is one of the most common inherited forms of ataxia and most frequently affects people of Portuguese descent.

The UT Southwestern researchers previously had found that calcium flow within nerve cells is disrupted in Huntington’s disease. The latest findings, appearing in the Nov. 26 issue of the Journal of Neuroscience, suggest that SCA3, which is caused by a genetic defect similar to the one found in Huntington’s, involves the same “deranged calcium signaling,” researchers said.

Both SCA3 and Huntington’s are caused by repeating segments of DNA, although the repeats associated with each disease appear in different genes that code for different proteins. The genetic mutations cause repeated units of the amino acid glutamine to appear in the respective proteins. The more repeats there are, the earlier the onset of the disease.

In Huntington’s disease the mutated protein is Huntingtin; in SCA3 it is ataxin-3.

The researchers determined that the mutant human ataxin-3 activates a molecule that acts as a channel in the membrane of a sequestered chamber inside cells called the endoplasmic reticulum, or ER. The channel then releases calcium into the cell as a whole. Normal ataxin-3 did not activate the channel or cause calcium release.

The researchers also found that cells from a person with SCA3 showed abnormally high levels of calcium release when treated with bradykinin, a substance that also activates the calcium channel.

Such abnormal calcium release is toxic to cells and results in impaired motor function, said Dr. Ilya Bezprozvanny, professor of physiology at UT Southwestern and senior author of the study. “We’re generalizing the idea of calcium toxicity for this group of diseases, which are called polyglutamine expansion disorders,” he said.

The researchers also studied mice that had been genetically engineered to overexpress the human ataxin-3 protein containing excessive glutamine repeats. The mutant mice performed poorly on tests of motor coordination compared with normal mice and displayed age-dependent neuronal loss in the same brain regions that are affected in SCA3 patients.

To test whether blocking calcium release would alleviate symptoms in the mice, the researchers treated them for a year with dantrolene, a drug that blocks excessive calcium release from the ER in skeletal muscle cells. Dantrolene is approved for use in humans as a one-time emergency treatment for a reaction to anesthesia.

Treatment with dantrolene improved the coordination of the mutant mice and slowed brain atrophy.

Dantrolene is not suitable for long-term use in humans, however, because of side effects that can potentially harm the liver and the heart and cause neurological problems, said Dr. Bezprozvanny.

“The take-home message is not so much that dantrolene is the solution for treating SCA3, but that this shows a direction for research into a better drug to block similar targets with fewer side effects,” Dr. Bezprozvanny said.

The researchers now are studying whether blocking calcium release from the endoplasmic reticulum also can improve function in mouse models of Huntington’s and other neurodegenerative diseases such as spinocerebellar ataxia type 2 and Alzheimer’s disease.

Other UT Southwestern researchers involved in the study were Dr. Xi Chen, postdoctoral researcher in physiology; Dr. Tie-Shan Tang, instructor of physiology; Dr. Huiping Tu, former instructor of physiology; graduate student Omar Nelson; and Dr. Robert Hammer, professor of biochemistry. Researchers from Brunel University in London and RIKEN Brain Science Institute in Japan also participated.

The study was funded by the National Institutes of Health, the Robert A. Welch Foundation, the McKnight Endowment Fund for Neuroscience, the National Ataxia Foundation, Ataxia UK, Ataxia MJD Research Project Inc. and MEXT of Japan.

Dr. Ilya Bezprozvanny -- http://www.utsouthwestern.edu/findfac/professional/0,2356,20034,00.html

Aline McKenzie | Newswise Science News
Further information:
http://www.utsouthwestern.edu
http://www.utsouthwestern.edu/findfac/professional/0,2356,20034,00.html

More articles from Health and Medicine:

nachricht Hot cars can hit deadly temperatures in as little as one hour
24.05.2018 | Arizona State University

nachricht 3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

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...

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

If solubilty is the problem - Mechanochemistry is the solution

25.05.2018 | Life Sciences

Investigating cell membranes: researchers develop a substance mimicking a vital membrane component

25.05.2018 | Interdisciplinary Research

When corals eat plastics

24.05.2018 | Ecology, The Environment and Conservation

VideoLinks
Science & Research
Overview of more VideoLinks >>>