Featured Research

from universities, journals, and other organizations

Potential drug for speeding up cellular recycling

Date:
March 13, 2012
Source:
University of Michigan
Summary:
Cell biologists have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

This microscope image shows many enlarged lysosomes inside a mouse skin cell. Lysosomes are the cell's recycling centers.
Credit: Xiang Wang and Haoxing Xu, University of Michigan

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.

"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.


Story Source:

The above story is based on materials provided by University of Michigan. Note: Materials may be edited for content and length.


Journal Reference:

  1. Dongbiao Shen, Xiang Wang, Xinran Li, Xiaoli Zhang, Zepeng Yao, Shannon Dibble, Xian-ping Dong, Ting Yu, Andrew P. Lieberman, Hollis D. Showalter, Haoxing Xu. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nature Communications, 2012; 3: 731 DOI: 10.1038/ncomms1735

Cite This Page:

University of Michigan. "Potential drug for speeding up cellular recycling." ScienceDaily. ScienceDaily, 13 March 2012. <www.sciencedaily.com/releases/2012/03/120313121721.htm>.
University of Michigan. (2012, March 13). Potential drug for speeding up cellular recycling. ScienceDaily. Retrieved September 23, 2014 from www.sciencedaily.com/releases/2012/03/120313121721.htm
University of Michigan. "Potential drug for speeding up cellular recycling." ScienceDaily. www.sciencedaily.com/releases/2012/03/120313121721.htm (accessed September 23, 2014).

Share This



More Health & Medicine News

Tuesday, September 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Liberia Pleads for Help to Fight Ebola

Liberia Pleads for Help to Fight Ebola

AP (Sep. 22, 2014) Liberia's finance minister is urging the international community to quickly follow through on pledges of cash to battle Ebola. Bodies are piling up in the capital Monrovia as the nation awaits more help. (Sept. 22) Video provided by AP
Powered by NewsLook.com
Ebola Doctor Says Border Controls Critical

Ebola Doctor Says Border Controls Critical

AP (Sep. 22, 2014) A Florida doctor who helped fight the expanding Ebola outbreak in West Africa says the disease can be stopped, but only if nations quickly step up their response and make border control a priority. (Sept. 22) Video provided by AP
Powered by NewsLook.com
Global Ebola Aid Increasing But Critics Say It's Late

Global Ebola Aid Increasing But Critics Say It's Late

Newsy (Sep. 21, 2014) More than 100 tons of medical supplies were sent to West Africa on Saturday, but aid workers say the global response is still sluggish. Video provided by Newsy
Powered by NewsLook.com
Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins