Last Month's Most Accessed Feature: Amyotrophic lateral sclerosis: NMR spots atomic changes

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  • Published: Mar 1, 2018
  • Categories: NMR Knowledge Base
thumbnail image: Last Month's Most Accessed Feature: Amyotrophic lateral sclerosis: NMR spots atomic changes


The hnRNPA2 protein forms liquid droplets in a test tube as seen by light microscopy. These structures let the researchers test how disease mutations and functional modifications change the behavior of the proteins with atomistic detail. Credit: Veronica Ryan/Brown University

Nuclear magnetic resonance (NMR) spectroscopy has been used to reveal for the first time the atom-by-atom changes that take place in a family of proteins associated with amyotrophic lateral sclerosis (ALS). This group of lethal brain disorders as well as frontotemporal dementia and degenerative diseases of muscle and bone. Details are reported in the journal Molecular Cell.

ALS, known in the UK as motor neurone disease (MND) and often in the USA as Lou Gehrig's disease, causes the death of neurons involved in voluntary muscle control. This leads to stiff muscles, muscle twitching, and ultimately such severe weakness that the sufferer becomes immobile as muscles waste away, or atrophy. The condition leads to difficulty in speaking, swallowing, and ultimately breathing. Premature death is common in ALS. A hereditary form affects between 5 and 10 of every hundred patients, but the cause of the condition in the other 90 to 95% of instance is yet to be determined.

The long-term goal of research into ALS is to find targets in the cellular pathways for pharmaceutical intervention that might moderate symptoms and perhaps even postpone the inevitable. It might even be possible to develop drugs or other therapies to precluded development of the disease. Nicolas Fawzi of Brown University explains that, "There is currently no therapy or cure for ALS and frontotemporal dementia. We are pursuing new hypotheses and angles to fight these illnesses."

Protein association

Fawzi and his colleagues explain that many proteins associated with ALS, frontotemporal dementia and other diseases have within their amino acid sequence "low-complexity" domains. Compared to the best-understood proteins in the cell, which are generally ordered and static in structure, the low-complexity domains within these proteins are fluxional and disordered; they have no rigid structure and remain flexible within the cell until cued into action. Of course, in non-disease states, such low-complexity domains within proteins actually help them perform their normal functions, such as assembling into liquid-like droplets, to allow critical cellular processes, such as RNA processing, to take place.

However, when low-complexity domains go awry, as in disease, they transform into inclusions, intractable and accumulating knots or clumps that then underlie the damage to neurons and other cells that lead to the symptoms of those diseases. In certain cancers, low-complexity domains are improperly attached to other proteins that may then incorrectly form droplets in cellular locations, leading to mis-regulated expression of genes, Fawzi explains. "We're trying to understand why they change behaviour and aggregate, and how we can disrupt those processes," he adds.

In the present research, Fawzi and his colleagues have looked at the physical interactions and chemical changes within proteins associated with several cellular functions, including disease forms, and how still-healthy cells could try to temper it. "We show how small chemical changes -involving only a few atoms - lead to big changes in assembly and disease-associated aggregation," Fawzi explains. "These interactions are more dynamic and less specific than previously thought. A molecule does not take just one shape and bind to one shape but a molecule is flexible and interacts in flexible ways."

Neuronal function

The team has studied a particular protein, hnRNPA2, which is mutated in disease. This protein collects within organelles within the cell that lack a membrane. In this environment those low-complexity domains adhere to one another. The new work reveals several mechanistic details of how low-complexity domain of hnRNPA2 operates in this regard and how it leads to protein aggregation in disease. The team used NMR spectroscopy, computer simulations and microscopy to look at methylation of the amino acid arginine and how this small change common to a large family of proteins with low-complexity domains, changes the way in which otherwise "liquid" protein droplets become "solid" in disease.

The work may well explain several aspects of biomedical research into ALS and other diseases conducted over the last two decades looking at the role of the hnRNP family of proteins in neuronal function and neurodegeneration. "Because these low-complexity domains are too flexible to be directly targeted by standard drugs, finding out how cells use and tame these domains is a potential route to stopping their unwanted assembly in disease," Fawzi explains.

Related Links

Mol Cell 2018, online: "Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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