Gül Zerze, Lehigh University

How Mutations Disrupt ALS-linked Protein

Article
Brain & Nerve
Behavioral & Mental Health
+1
Contributed byKrish Tangella MD, MBASep 08, 2016

In amyotrophic lateral sclerosis, aggregates of the protein TDP-43 are almost always found in afflicted neurons and glial cells. Meanwhile, about 50 ALS-linked mutations are known to affect a particular region of TDP-43. Yet scientists have never understood how those two associations connect. A new study in the journal Structure shows how ALS mutations disrupt the protein at the atomic level, preventing it from executing its proper function and instead leading to those aggregates.

"We knew that part of TDP-43 builds up in aggregates and that there are 50 mutations in that domain, but we didn't know the job of that domain, how it goes wrong and why it aggregates," said study corresponding author Nicolas Fawzi, assistant professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown University.

In general, TDP-43 acts like a chaperone for RNA in a cell, binding to it, guiding its processing, transporting it to where it needs to go and regulating it, so that other proteins can be expressed properly. Using nuclear magnetic resonance, computer simulations and microscopy, Fawzi, Brown graduate student Alexander Conicella and colleagues at Lehigh University were able to show that under normal circumstances, TDP-43 molecules concentrate into little droplets, a process called "liquid-liquid phase separation." It's within these droplets that they could process and ferry RNA.

The team's focus was on a particular region of TDP-43, called the "C-terminal domain," which appeared to be crucial in the concentration of molecules that leads to phase separation.

"We were looking for a functional role for this part of the protein," Fawzi said "Its job can't just be to do nothing and then aggregate in disease."

The observations showed that the interactions and resulting concentration of TDP-43 molecules depend on a small corkscrew-shaped part of the protein's C-terminal domain termed a helix. The same sequence of DNA specifying that corkscrew shape has been exactly preserved by evolution in many vertebrate animals suggesting it has an important biological function.

What Fawzi and his teams observed is that as one TDP-43 molecule meets another, the corkscrews stabilize and lengthen, promoting a bond between them.

Finally, the team shows in the paper that the various ALS mutations disrupt this process, either by upsetting the formation of the corkscrews or their ability to lengthen and stabilize.

"Mutations in this [corkscrew] region blow that interaction up," Fawzi said.

The result is that the concentration and phase separation does not occur. Instead the proteins can combine in a more potentially harmful way -- in the aggregates seen in diseased neurons.

By ferreting out this mechanistic connection between the mutations, the loss of protein's proper phase separation behavior and how it frees molecules up to aggregate, the team shows how the mutations could lead to disease, Fawzi said.

"That might be one mechanism by which ALS mutation cause ALS -- by disrupting TDP-43's normal function," he said.

The paper further emphasizes the urgency of an overarching question in ALS. Only about 10 percent of ALS cases are traceable to a genetic cause. It remains unclear what's happening to disrupt TDP-43 in many cases when a known mutation is not the cause.

But now scientists have new a new set of data and an explanation of how TDP-43 appears to work and what can make it fail.

That's also important, Fawzi noted, because TDP-43 is implicated in other degenerative neural diseases as well.

"Given the recent evidence that TDP-43 also accumulates in Alzheimer's disease, understanding the role of TDP-43 is all the more urgent," he said.


The above post is reprinted from materials provided by Brown University.Note: Content may be edited for style and length.

Disclaimer: DoveMed is not responsible for the adapted accuracy of news releases posted to DoveMed by contributing universities and institutions.

Primary Resource:

Conicella, A. E., Zerze, G. H., Mittal, J., & Fawzi, N. L. (2016). ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure.

Was this article helpful

On the Article

Krish Tangella MD, MBA picture
Approved by

Krish Tangella MD, MBA

Pathology, Medical Editorial Board, DoveMed Team

0 Comments

Please log in to post a comment.

Related Articles

Test Your Knowledge

Asked by users

Related Centers

Loading

Related Specialties

Loading card

Related Physicians

Related Procedures

Related Resources

Join DoveHubs

and connect with fellow professionals

Related Directories

Who we are

At DoveMed, our utmost priority is your well-being. We are an online medical resource dedicated to providing you with accurate and up-to-date information on a wide range of medical topics. But we're more than just an information hub - we genuinely care about your health journey. That's why we offer a variety of products tailored for both healthcare consumers and professionals, because we believe in empowering everyone involved in the care process.
Our mission is to create a user-friendly healthcare technology portal that helps you make better decisions about your overall health and well-being. We understand that navigating the complexities of healthcare can be overwhelming, so we strive to be a reliable and compassionate companion on your path to wellness.
As an impartial and trusted online resource, we connect healthcare seekers, physicians, and hospitals in a marketplace that promotes a higher quality, easy-to-use healthcare experience. You can trust that our content is unbiased and impartial, as it is trusted by physicians, researchers, and university professors around the globe. Importantly, we are not influenced or owned by any pharmaceutical, medical, or media companies. At DoveMed, we are a group of passionate individuals who deeply care about improving health and wellness for people everywhere. Your well-being is at the heart of everything we do.

© 2023 DoveMed. All rights reserved. It is not the intention of DoveMed to provide specific medical advice. DoveMed urges its users to consult a qualified healthcare professional for diagnosis and answers to their personal medical questions. Always call 911 (or your local emergency number) if you have a medical emergency!