Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Protein aggregates in Lou Gehrig’s disease linked to neuron death

27.10.2005


French neurologist Jean-Martin Charcot first described amyotrophic lateral sclerosis (ALS) in 1869, but, nearly 140 years later, little is known about the cause of the devastating neurodegenerative disease, and there is no cure.



What is known about Lou Gehrig’s disease, as it is commonly called, is that misfolded and damaged proteins clump together in cells to form aggregates and motor neurons die. But scientists have long debated whether or not the protein aggregates actually kill the cells.

Now a research team at Northwestern University, using mammalian neurons and live-cell time-lapse spectroscopy, has become the first to clearly link the presence of the ALS-associated mutant SOD1 protein aggregates with neuronal cell death. This evidence could help explain the disease process and eventually lead to new therapeutics.


In the study, published this month in the Journal of Cell Biology, the scientists looked one at a time at neuronal cells expressing the mutant SOD1 protein and found that in cells where the protein accumulated and aggregates formed, 90 percent of the cells went on to die. (They died between six and 24 hours after aggregates were visually detected.) Cells that did not form aggregates did not die.

The study also provides a new understanding of the structure and composition of the deadly aggregates -- one of the first studies to do so.

"We found that these aggregates are quite peculiar and very different from the aggregates formed in Huntington’s disease," said Richard I. Morimoto, Bill A. and Gayle Cook Professor in Biological Sciences, who led the study. Morimoto is an expert in Huntington’s disease and on the cellular response to damaged proteins.

"In Huntington’s, the aggregate is very dense and impenetrable and binds irreversibly with other molecules in the cell," he said. "In ALS, the aggregates are amorphous, like a sponge. Other proteins can go through the structure and interact with it, which may help explain why mutant SOD1 is so toxic." Morimoto believes this surprising finding indicates that the structure of aggregates associated with other neurodegenerative diseases such as Parkinson’s and Alzheimer’s will be found to be different as well.

Looking at individual cells in a population, the researchers also found that cells side by side did different things. In cells expressing the same amount of damaged protein, some cells formed aggregates and died and others did not form aggregates and lived. Only a certain subset of at-risk cells went on to lose function and die.

"It would be terrifying if 100 percent of the cells expressing mutant proteins died," said Morimoto. "This means that in many cases the cell’s protective machinery suppresses the damaged proteins, keeping the cell healthy. This discovery will be important to scientists looking to develop genetic suppressors and therapeutics."

Morimoto’s team focused on SOD1 because it is a form of familial (hereditary) ALS in which a mutation in just one gene and its associated protein has devastating consequences to the cell. (Approximately 10 percent of ALS cases are familial.) This provides experimentalists with a powerful framework. For the other 90 percent the disease is not the result of one mutation but rather a series of many genetic events that debilitate motor neurons. With non-familial forms it is extremely difficult to design hypothesis-based experiments, said Morimoto.

The next question the researchers plan to address is what are the events that lead to cell death once mutant SOD1 protein aggregates form in the cell? This knowledge would help scientists identify small molecules that could halt, arrest or reverse the disease process.

In addition to Morimoto, other authors on the Journal of Cell Biology paper are Carina I. Holmberg, Soojin Kim, Gen Matsumoto (lead author) and Aleksandar Stojanovic, all formerly from Northwestern University.

Megan Fellman | EurekAlert!
Further information:
http://www.northwestern.edu

More articles from Life Sciences:

nachricht When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short
23.03.2017 | Institut für Pflanzenbiochemie

nachricht WPI team grows heart tissue on spinach leaves
23.03.2017 | Worcester Polytechnic Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short

23.03.2017 | Life Sciences

Researchers use light to remotely control curvature of plastics

23.03.2017 | Power and Electrical Engineering

Sea ice extent sinks to record lows at both poles

23.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>