ALS toxic protein study opens new door for drug discovery

Posted on Posted in Biotechnology, Medical News, Pioneering Technology

A new study provides the first evidence-based description of a type of protein clump thought to play an important role in ALS, or Lou Gehrig’s disease, by killing the nerve cells that control movement.

The researchers found trimers of tightly bound SOD1 protein were deadly to motor neuron-like cells, while non-clumped SOD1 protein was not.

Writing in the Proceedings of the National Academy of Sciences, the team from the University of North Carolina at Chapel Hill also explain how theirs is the first evidence that the protein clumps are toxic to motor neurons – the type of nerve cells that die in patients with ALS.

Senior author Nikolay Dokholyan, a professor of biochemistry and biophysics, says:

“This study is a big breakthrough because it sheds light on the origin of motor neuron death and could be very important for drug discovery.”

Amyotrophic lateral sclerosis (ALS) is a group of diseases that gradually destroy motor neurons – the nerve cells that control muscle movement. It first came to public attention when the American baseball player Lou Gehrig died of the disease in 1941.

Patients with ALS suffer gradual paralysis and early death as their motor neurons die off and they lose their ability to move, speak, swallow and breathe.

The study concerns a subset of ALS that affects around 1-2% of patients. Patients in this type of ALS have variations in a protein called SOD1. However, the researchers note that toxic SOD1 protein clumps can also form in patients without the mutated form.

In their study, the team found SOD1 first collects into clumps of three protein molecules, or “trimers.” When they tested them, they found the trimers could kill lab-grown cells similar to motor neurone.

Instability of SOD1 clumps could explain toxicity

First author Dr. Elizabeth Proctor, who worked on the study as a graduate student in Prof. Dokholyan’s lab, says the discovery about SOD1 trimers is important, because before this, nobody knew exactly which toxic interactions were responsible for killing motor neurons in ALS. She adds:

“Knowing what these trimers look like, we can try to design drugs that would stop them from forming, or sequester them before they can do damage. We are very excited about the possibilities.”

Clues about SOD1 clumps in ALS emerged in the early 1990s, but because the clumps thought to be toxic are unstable and disintegrate quickly, it has been very difficult to study them.

Now, the researchers believe it is the instability of SOD1 clumps that makes them toxic. Dr. Proctor says this is what “makes them more reactive with parts of the cell that they should not be affecting.”

The study is the first to show what these fleeting clumps of SOD1 protein look like, and thus how they could be affecting the nerve cells.

The team combined computer modeling and live cell experiments to make their discovery. They developed a custom algorithm to map the trimer structure of SOD1 and then developed methods to test its effect on motor neuron-like cells grown in the lab.

Using these methods, they found that SOD1 protein tightly bound as trimers was deadly to motor neuron-like cells, while non-clumped SOD1 protein was not.

The team now wants to find out what holds the trimers together, as this could be important for developing drugs for breaking them up or stopping them forming in the first place.

They believe the findings could also be important for research on other neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Prof. Dokholyan concludes:

“What we have found here seems to corroborate what is known about Alzheimer’s already, and if we can figure out more about what is going on here, we could potentially open up a framework to be able to understand the roots of other neurodegenerative diseases.”

Credit: Catharine Paddock PhD. http://www.medicalnewstoday.com/articles/304608.php

Picture Credit: http://www.medicalnewstoday.com

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