Featured Research

from universities, journals, and other organizations

Alzheimer's Protein Jams Mitochondria Of Affected Cells; Resulting 'Energy Crisis' Kills Neurons

Date:
April 15, 2003
Source:
University Of Pennsylvania
Summary:
Opening a new front in the battle against Alzheimer's disease, scientists at the University of Pennsylvania have found that a protein long associated with the disease inflicts grave damage in a previously unimagined way: It seals off mitochondria in affected neurons, resulting in an "energy crisis" and buildup of toxins that causes cells to die.

PHILADELPHIA -- Opening a new front in the battle against Alzheimer's disease, scientists at the University of Pennsylvania have found that a protein long associated with the disease inflicts grave damage in a previously unimagined way: It seals off mitochondria in affected neurons, resulting in an "energy crisis" and buildup of toxins that causes cells to die. This pathway, the first specific biochemical explanation for pathologies associated with Alzheimer's, is detailed in the April 14 issue of the Journal of Cell Biology.

While the normal function of the amyloid precursor protein (APP) remains unknown, senior author Narayan G. Avadhani and his colleagues have determined that a mere 50-amino-acid stretch of the protein wreaks havoc by essentially starving mitochondria and the cells they nourish.

"We found that when APP leaves the nucleus, it can be directed both to mitochondria and to the endoplasmic reticulum," said Avadhani, professor of biochemistry and chair of the Department of Animal Biology in Penn's School of Veterinary Medicine. "APP has an acidic, negatively charged region that causes it to jam irreversibly while traversing protein transport channels in the mitochondrial membrane. This hampers, and eventually completely blocks, mitochondria's ability to import other proteins and produce cellular energy."

As if suffocating the cell's power plant weren't enough, jammed APP proteins also damaged the mouse neurons studied by Avadhani and co-author Hindupur K. Anandatheerthavarada in a second way. The end of the protein left dangling outside the mitochondrion contains a toxic product called A-Beta. The Penn researchers found that this toxin, a known component of the brain plaques and tangles that are a hallmark of Alzheimer's, is cleaved from the rest of the immobilized protein and accumulates in the cell.

"Researchers have observed many biochemical and biophysical phenomena associated with Alzheimer's disease," said Anandatheerthavarada, research assistant professor of biochemistry and the paper's first author, "but it has remained unclear whether these are causes of Alzheimer's or merely side effects. The pathway we observed, which leads directly to common symptoms, is the first with a demonstrated ability to cause the neuronal death associated with Alzheimer's disease."

The results are consistent with the progressive nature of Alzheimer's and other neurodegenerative diseases, the scientists said. As pores in the mitochondrial membrane clog with proteins -- inaccessible to enzymes that might normally degrade them -- cellular function is steadily and inevitably reduced until cell death, reached when APP succeeds in suffocating all the cell's mitochondria.

Avadhani and Anandatheerthavarada's results put a dent in cell biology dogma, which holds that each of the proteins produced in the nucleus can be directed to only one location in the cell. In APP's case, the Penn scientists have shown the targeting sequence within the protein's N-terminal directs it to at least two locations, the mitochondrion and endoplasmic reticulum.

The implication of mitochondrial failure is unexpected because most Alzheimer's researchers, believing the mitochondrion was not on APP's itinerary, have focused on the protein's effects on other organelles. In fact, Avadhani and Anandatheerthavarada found that mitochondria appear to be the only organelles whose membranes have trouble handling APP.

It remains unclear whether APP gets stuck in mitochondria's protein entryways because of its negative charge or bulkiness attributable to improper protein folding. Avadhani and Anandatheerthavarada plan to study the question, which could eventually yield medications to correct the problem.

"A mutant version of APP without the region that's prone to jamming passes into the mitochondria without a hitch," Avadhani said. "This suggests that pharmaceuticals could be developed to fix this domain, either by neutralizing its charge or folding it more tightly."

Avadhani and Anandatheerthavarada were joined in this research by Gopa Biswas and Mary-Anne Robin, both of Penn's Department of Animal Biology. Their work was funded by the National Institutes of Health.


Story Source:

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


Cite This Page:

University Of Pennsylvania. "Alzheimer's Protein Jams Mitochondria Of Affected Cells; Resulting 'Energy Crisis' Kills Neurons." ScienceDaily. ScienceDaily, 15 April 2003. <www.sciencedaily.com/releases/2003/04/030415084359.htm>.
University Of Pennsylvania. (2003, April 15). Alzheimer's Protein Jams Mitochondria Of Affected Cells; Resulting 'Energy Crisis' Kills Neurons. ScienceDaily. Retrieved August 2, 2014 from www.sciencedaily.com/releases/2003/04/030415084359.htm
University Of Pennsylvania. "Alzheimer's Protein Jams Mitochondria Of Affected Cells; Resulting 'Energy Crisis' Kills Neurons." ScienceDaily. www.sciencedaily.com/releases/2003/04/030415084359.htm (accessed August 2, 2014).

Share This




More Mind & Brain News

Saturday, August 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Work Can Be Stressful, But Is Unemployment Worse?

Work Can Be Stressful, But Is Unemployment Worse?

Newsy (Aug. 1, 2014) A new study shows stress at work can be hard on your health, but people who are unemployed might be at even greater risk of health problems. Video provided by Newsy
Powered by NewsLook.com
Google (Kind Of) Complies With 'Right To Be Forgotten Law'

Google (Kind Of) Complies With 'Right To Be Forgotten Law'

Newsy (July 31, 2014) Google says it is following Europe's new "Right To Be Forgotten Law," which eliminates user information upon request, but only to a certain degree. Video provided by Newsy
Powered by NewsLook.com
Stroke Signs: Three Hour Deadline

Stroke Signs: Three Hour Deadline

Ivanhoe (July 31, 2014) Sometimes the signs of a stroke are far from easy to recognize. Learn from one young father’s story on the signs of a stroke. Video provided by Ivanhoe
Powered by NewsLook.com
Grain Brain May Be Harming Us

Grain Brain May Be Harming Us

Ivanhoe (July 31, 2014) Could eating carbohydrates be harmful to our brain health? Find out what one neurologist says about changing our diets. Video provided by Ivanhoe
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:
from the past week

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