Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Biologists Find Potential Drug That Speeds Cellular Recycling

14.03.2012
A University of Michigan cell biologist and his colleagues have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, as well as more common neurodegenerative diseases like Alzheimer's and Parkinson's, said Haoxing Xu, who led a U-M team that reported its findings March 13 in the online, multidisciplinary journal Nature Communications.


Image credit: Xiang Wang and Haoxing Xu, University of Michigan.

This microscope image shows many enlarged lysosomes inside a mouse skin cell. Lysosomes are the cell's recycling centers.

"The implications are far-reaching," said Xu, an assistant professor of molecular, cellular and developmental biology. "We have introduced a novel concept—a potential drug to increase clearance of cellular waste—that could have a big impact on medicine."

Xu cautioned, however, that the studies are in the early, basic-research stage. Any drug that might result from the research is years away.

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.

Inside the trillions of cells that make up the human body, the job of chopping up and shipping worn-out cellular components falls to the lysosomes. The lysosomes—there are several hundred of them in each cell—use a variety of digestive enzymes to disassemble used-up proteins, fatty materials called lipids, and discarded chunks of cell membrane, among other things.

Once these materials are reduced to basic biological building blocks, the cargo is shipped out of the lysosome to be reassembled elsewhere into new cellular components.

The steady flow of the materials through and out of the lysosome, called vesicular trafficking, is essential for the health of the cell and the entire organism. If trafficking slows or stops, the result is a kind of lysosomal constipation that can cause or contribute to a variety of diseases, including a group of inherited metabolic disorders called lipid storage diseases. Niemann-Pick is one of them.

In previous studies, Xu and his colleagues showed that proper functioning of the lysosome depends, in part, on the timely flow of calcium ions through tiny, pore-like gateways in the lysosome's surface membrane called calcium channels.

If the calcium channels get blocked, trafficking throughout the lysosome is disrupted and loads of cargo accumulate to unhealthy levels, swelling the lysosome to several times its normal size.

Xu and his colleagues previously determined that a protein called TRPML1serves as the calcium channel in lysosomes and that a lipid known as PI(3,5)P2 opens and closes the gates of the channel. Human mutations in the gene responsible for making TRPML1 cause a 50 to 90 percent reduction in calcium channel activity.

In their latest work, aided by a new imaging method used to study calcium-ion release in the lysosome, Xu and his colleagues show that TRPML1-mediated calcium release is dramatically reduced in Niemann-Pick and mucolipidosis Type IV disease cells.

More importantly, they identify a synthetic small molecule, ML-SA1, that mimics the lipid PI(3,5)P2 and can activate the lysosome's calcium channels, opening the gates and restoring the outward flow of calcium ions.

When ML-SA1 was introduced into mouse cells and human Niemann-Pick Type C cells donated by patients, the increased flow through the lysosome's calcium channels was sufficient to speed trafficking and reduce lysosome storage.

Xu and his colleagues believe it might be possible to use ML-SA1 as a drug to activate lysosome calcium channels and restore normal lysosome function in lipid storage diseases like Niemann-Pick. The same approach might also be used to treat Alzheimer's disease and Parkinson's, neurodegenerative diseases that involve lysosome trafficking defects.

Such studies might also provide insights into the aging process, which involves the very slow decline in the lysosomes' ability to chop up and recycle worn-out cellular parts.

"The idea is that for lysosome storage diseases, neurodegenerative diseases and aging, they're all caused or worsened by very reduced or slow trafficking in the cellular recycling center," Xu said.

Next step? The researchers hope to administer ML-SA1 to Niemann-Pick and mucolipidosis Type IV mice to determine if the molecule alleviates symptoms.

In Niemann-Pick disease, harmful quantities of lipids accumulate in the spleen, liver, lungs, bone marrow and brain. The disease has four related types. Type A, the most severe, occurs in early infancy and is characterized by an enlarged liver and spleen, swollen lymph nodes and profound brain damage by the age of 6 months. Children with this type rarely live beyond 18 months. There is currently no cure for Niemann-Pick disease.

The first author of the Nature Communications paper is Dongbiao Shen, a graduate student research assistant in the U-M Department of Molecular, Cellular and Developmental Biology.

Other authors, in addition to Xu, are Xiang Wang, Xinran Li, Xiaoli Zhang, Zepeng Yao, Shannon Dibble and Xian-ping Dong of the U-M Department of Molecular, Cellular and Developmental Biology; Ting Yu and Andrew Lieberman of the U-M Medical School's Department of Pathology; and Hollis Showalter of the Vahlteich Medicinal Chemistry Core in the U-M College of Pharmacy's Department of Medicinal Chemistry.

The work was supported by grants from the National Institutes of Health and the ML4 Foundation.

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

U-M Department of Molecular, Cellular and Developmental Biology: www.mcdb.lsa.umich.edu

Jim Erickson | Newswise Science News
Further information:
http://www.umich.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton 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: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>