Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Opening the Gate to the Cell's Recycling Center

16.07.2010
In cells, as in cities, disposing of garbage and recycling anything that can be reused is an essential service. In both city and cell, health problems can arise when the process breaks down.

New research by University of Michigan cell biologist Haoxing Xu and colleagues reveals key details about how the cell's garbage dump and recycling center, the lysosome, functions. These insights, which may lead to better understanding of conditions such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and Charcot-Marie-Tooth (CMT) disease, suggest new avenues of treatment for these and other diseases that cause nerves and muscles to malfunction.

The research, published this week in the online, multidisciplinary journal Nature Communications, focused on gateways called calcium channels in the lysosome membrane. Calcium channels, which also are found in the membranes surrounding muscle and nerve cells, are made of proteins that respond to signals in the form of electrical impulses. When the proper signal comes along, the proteins open the channel, allowing calcium to pass through. The calcium, in turn, triggers some vital process such as muscle contraction or the release of a hormone or neurotransmitter (a chemical messenger involved in nerve transmission).

Scientists know a lot about the workings of calcium channels in the surfaces of muscle and nerve cells, but understanding what goes in the lysosome---a tiny pouch hidden inside the cell---has been a challenge, said Xu. Consequently, the exact identity of the protein involved and how it becomes activated have remained a mystery.

To explore the channel and its workings, Xu's group modified a technique known as the patch clamp, in which a scaled-down pipette and electrodes are attached to a cell membrane to record the activity of one or more proteins making up the channel. With their modification, which they call the lysosome patch clamp, the researchers determined that a protein called TRPML1 serves as the calcium channel in lysosomes and that a lipid known as PI(3,5)P2 carries the signal that activates the protein.

This particular protein and lipid aren't obscure characters previously unknown to science. A mutation in the gene that produces TRPML1 is known to cause Type IV mucolipidosis (ML4), a genetic disorder that affects mainly Jews of Eastern European background and results in mental retardation, poor vision and diminished motor abilities. And mutations in the enzymes needed to make PI(3,5) P2 cause a variety of neurodegenerative diseases including ALS and CMT.

The protein TRPML1 also is of interest because of the unusual way it does its work.

"While other channel proteins are in the 'passenger' seats of the membrane traffic, TRPML1 is in the 'driver' seat," said Xu, an assistant professor of molecular, cellular and developmental biology. This suggests that manipulating TRPML1 channel activity using channel activators or inhibitors could affect membrane traffic.

"If you can activate the channel, it might be possible to overcome the membrane traffic defects caused by the disease-causing mutations. Luckily, small-molecule chemicals that can stimulate TRPML1 channel activity are already available, " Xu said.

He and collaborator Miriam Meisler, a human genetics professor at the U-M Medical School, have experiments underway to see if they can prevent or reverse the course of disease in a mouse model of ALS by increasing activity of the TRPML1 channel.

If the strategy is successful, Xu hopes to explore its use in treating other neurological diseases.

"If the system we're studying turns out to be compromised in more common diseases, the method of increasing channel activity could have important implications for their treatment," he said.

Xu's coauthors on the Nature Communications paper are postdoctoral fellows Xian-ping Dong, Xiping Cheng and Yanling Zhang; graduate students Dongbiao Shen, Xiang Wang, and Qi Zhang; and undergraduate students Taylor Dawson and Xinran Li, all at U-M; Lois Weisman, who is the Sarah Winans Newman Collegiate Professor in the Life Sciences at U-M; and Markus Delling of Children's Hospital Boston.

The research was funded by the U-M Department of Molecular, Cellular & Developmental Biology; the U-M Biological Sciences Scholars Program; the U-M Initiative on Rare Disease Research, the Michigan Alzheimer's Disease Research Center, the National Multiple Sclerosis Society and the National Institutes of Health.

More information:

Haoxing Xu: http://www.mcdb.lsa.umich.edu/faculty_haoxingx.html

Nature Communications: http://www.nature.com/ncomms/index.html

Nancy Ross-Flanigan | Newswise Science News
Further information:
http://www.umich.edu

More articles from Life Sciences:

nachricht Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Corporate coworking as a driver of innovation

22.11.2017 | Business and Finance

PPPL scientists deliver new high-resolution diagnostic to national laser facility

22.11.2017 | Physics and Astronomy

Quantum optics allows us to abandon expensive lasers in spectroscopy

22.11.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>