Researchers look to worms for a new model of a peripheral nervous system disease

August 7, 2018, The Scripps Research Institute
The study leader Sandra Encalada, Ph.D., Arlene and Arnold Goldstein Assistant Professor of Molecular Medicine at Scripps Research. Credit: Scripps Research

Studying transthyretin amyloidoses-a group of progressive nerve and cardiac degenerative diseases caused by the buildup of misfolded transthyretin (TTR) proteins in the body-has long been hampered by the lack of animal models of the disease. Mice, for instance, don't show the same symptoms as humans, even when misfolded TTR accumulates in their organs.

Now, scientists at Scripps Research have discovered that Caenorhabditis elegans, a nematode, or microscopic roundworm, develops similar nerve damage to patients when their muscle cells are genetically engineered to produce TTR.

"This is really the first model that recapitulates what we see in humans both with regards to the molecular and cellular signatures of the disease, and the symptoms," says Sandra Encalada, Ph.D., Arlene and Arnold Goldstein Assistant Professor of Molecular Medicine at Scripps Research.

The new C. elegans model, which Encalada and her team described recently in the journal Proceedings of the National Academy of Sciences, has already let Scripps Research scientists make inroads into understanding how TTR proteins become misfolded and aggregate to cause disease in neurons.

In humans, TTR is produced and secreted by the liver, where sets of four copies of the assemble together into tetrameric TTR that's sent out into the bloodstream. In the blood, TTR normally binds and transports the thyroid hormone thyroxine, as well as vitamin A bound to retinol binding protein to deliver them throughout the body.

But there's a ticking clock: the four TTR copies also fall apart over time, and then, in some cases, change their conformation or shape and regroup or misassemble into larger aggregates that deposit in tissues. There is genetic and pharmacologic evidence that this process causes neurodegeneration.

People can suffer from a variety of diseases based on the sequence of TTR that misfolds and misassembles and depending on where misfolded TTR aggregates accumulate. In the two most common forms of TTR amyloid disease, the protein accumulates in the heart-causing cardiac symptoms-or in the nerves of the legs and arms-causing a peripheral neuropathy. While some people who develop these diseases have mutations in their TTR protein, making them more prone to aggregate, others have normal TTR that can also misfold and misassemble.

"We know quite a bit about the molecular dynamics of how TTR comes apart and how it creates aggregates," says Encalada. "But until now we didn't have any mechanism at the cellular level. How do heart or nerve cells degenerate when TTR aggregates?" Scientists working with dozens of rodent and fruit fly models have failed to replicate what is seen in humans with these conditions.

In an attempt to answer these questions, Encalada and her collaborators engineered C. elegans to produce TTR in their muscle cells. They then tested the bodies of the nematodes for the presence of TTR. The protein, they showed, was secreted out of the muscle cells and into the worms' body cavity. And just as in humans, the TTR broke down from tetramers and converted into misfolded and aggregated TTR molecules over the course of about a week.

When the researchers gave the nematodes a mutated version of TTR known to cause progressive peripheral neuropathy in humans, the worms showed abnormal growth of sensory nerve cells, and lost the ability to feel pain and temperature -the same impairments that are seen in humans. Moreover, when the worms were treated with drugs that ameliorate TTR peripheral neuropathy in humans, the worms showed dramatic improvement of the aforementioned degenerative phenotypes.

Encalada's team tracked where the TTR was going in the worms' bodies, and they found that tetramers of the protein secreted from the muscle, accumulated in the cells responsible for breaking down the body's waste. These cells, the researchers showed, were degrading TTR and preventing the production of toxic aggregates. Deleting these cells enhanced the aggregation of TTR and increased the percentage of animals that had signs of nerve , including loss of pain sensation, as observed in humans.

"The big picture is that we were able to modulate levels of TTR degradation without touching neurons or the producing TTR," says Encalada. "In humans, being able to tweak levels of TTR degradation could act as a means of stopping TTR toxicity."

More work is needed to determine whether the observations in C. elegans can be recapitulated in humans regarding the ability of specific to degrade TTR, but Encalada is hopeful that the new animal models will fuel more research into TTR-linked diseases. In addition, she says, the overall findings on the link between protein degradation and nerve toxicity could translate to other neurodegenerative diseases, including Alzheimer's.

Explore further: Molecular culprits of protein aggregation in ALS and FTLD

More information: Kayalvizhi Madhivanan et al, Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1801117115

Related Stories

Molecular culprits of protein aggregation in ALS and FTLD

July 19, 2018
The mutated and aggregated protein FUS is implicated in two neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Using a newly developed fruit fly model, researchers ...

Novel therapy delays muscle atrophy in Lou Gehrig's disease model

July 12, 2018
Supplementing a single protein found in the spinal cord could help prevent symptoms of Lou Gehrig's disease, according to a new study out of Case Western Reserve University School of Medicine. Researchers found high levels ...

Effects of amyloid beta plaque on different brain cells

April 16, 2018
Amyloid beta, a protein linked with Alzheimer's disease, has different properties in different cell types in the brains of fruit flies. This is the conclusion of a study led by researchers at Linköping University in Sweden. ...

Researchers uncover culprit in Parkinson's brain cell die-off

March 5, 2018
An estimated 10 million people worldwide are living with Parkinson's disease—an incurable neurodegenerative disorder that leads to an increasing loss of motor control.

Study sheds light on link between diseases like Alzheimer's and normal aging in the brain

May 17, 2017
In a recent Frontiers in Aging Neuroscience paper, Drs. Della David and Frank Baumann together with their teams at the German Center for Neurodegenerative Diseases and Hertie Institute, showed that changes in proteins associated ...

Recommended for you

New brain imaging research shows that when we expect something to hurt it does, even if the stimulus isn't so painful

November 14, 2018
Expect a shot to hurt and it probably will, even if the needle poke isn't really so painful. Brace for a second shot and you'll likely flinch again, even though—second time around—you should know better.

New clues to the origin and progression of multiple sclerosis

November 13, 2018
Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The ...

Mutations, CRISPR, and the biology behind movement disorders

November 12, 2018
Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the ...

In live brain function, researchers are finally seeing red

November 12, 2018
For years, green has been the most reliable hue for live brain imaging, but after using a new high-throughput screening method, researchers at the John B. Pierce Laboratory and the Yale School of Medicine, together with collaborators ...

Concussion tied to suicide risk

November 12, 2018
(HealthDay)—People who have experienced either a concussion or a mild traumatic brain injury are twice as likely to commit suicide than others, a new review suggests.

Autism is associated with zinc deficiency in early development—now a study links the two

November 9, 2018
The emergence of autism in children has not only been linked to genes encoding synaptic proteins—among others—but also environmental insults such as zinc deficiency. Although it is unclear whether zinc deficiency contributes ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.