Model for peripheral nerve disease developed in worm

A team from the US have discovered that the nematode, Caenorhabditis elegans, develops similar nerve damage to human patients in a new model of a peripheral nervous system disease.

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 human 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 Dr Sandra Encalada, 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 protein 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.

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