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.

Blockade in cellular waste disposal: Scientists show how protein aggregates disrupt the molecular balance of the cell

June 21, 2013
Proteins can only perform their complex functions in the cell when they assume a specific three-dimensional structure for each respective task. Because misfolded proteins are often toxic, they are immediately refolded or ...

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

Breast milk may be best for premature babies' brain development

September 21, 2018
Babies born before their due date show better brain development when fed breast milk rather than formula, a study has found.

Early warning sign of psychosis detected

September 21, 2018
Brains of people at risk of psychosis exhibit a pattern that can help predict whether they will go on to develop full-fledged schizophrenia, a new Yale-led study shows. The findings could help doctors begin early intervention ...

White matter repair and traumatic brain injury

September 20, 2018
Traumatic brain injury (TBI) is a leading cause of death and disability in the U.S., contributing to about 30 percent of all injury deaths, according to the CDC. TBI causes damage to both white and gray matter in the brain, ...

'Gut sense' is hardwired, not hormonal

September 20, 2018
If you've ever felt nauseous before an important presentation, or foggy after a big meal, then you know the power of the gut-brain connection.

Genomic dark matter activity connects Parkinson's and psychiatric diseases

September 20, 2018
Dopamine neurons are located in the midbrain, but their tendril-like axons can branch far into the higher cortical areas, influencing how we move and how we feel. New genetic evidence has revealed that these specialized cells ...

Gut branches of vagus nerve essential components of brain's reward and motivation system

September 20, 2018
A novel gut-to-brain neural circuit establishes the vagus nerve as an essential component of the brain system that regulates reward and motivation, according to research conducted at the Icahn School of Medicine at Mount ...

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.