A worm, barely visible, may shed new light on the basic processes underlying amyotrophic lateral sclerosis (ALS), according to research funded by The ALS Association (ALSA). Investigator Richard Morimoto, Ph.D., has built on ability of the millimeter long worm, C. elegans, to live in a lab dish, revealing fundamental processes at work. Morimoto and his team have now created a model in the worm of aspects of ALS that could lead to new ways to screen for therapeutics for the disease.
In inherited forms of ALS, a mutation alters a particular protein. The worm can be engineered to make within its cells the mutant form of copper/zinc superoxide dismutase (SOD1) present in some cases of inherited ALS. The worm, which is transparent, shows the mutant protein as clumps within it. The worm also becomes sluggish with a change in the temperature of its surroundings. Such changes give visible evidence of the altered SOD1 protein and provide useful measures to aid the search for potential ALS drugs.
Morimoto, at Northwestern University in Evanston, Ill., is funded through the ALSA-initiated granting process to develop the worm as a potential screen for therapeutics.
Sticky ProteinClumps of damaged protein are a hallmark of ALS. Protein aggregates are evident in the mouse model that expresses mutant SOD1. The abnormal deposits of protein do contain mutant SOD1 in the mice. Evidently, with the mutation, SOD1 changes from its normal shape to a form that tends to stick together, at least in the mutant mice.
Abnormal deposits of protein are a phenomenon common to many neurodegenerative diseases. The commonalities have brought together researchers with the hope to find common paths to treatments. Morimoto had developed a worm model of Huntington’s disease when ALSA recruited him to the ALS effort.
Our 30 trillion cells produce more than a trillion different proteins. Proteins often manifest damage by clumping and sticking together. With disease, aging, or trauma, proteins in all of our cells can have damage that either can be salvaged, or cannot be undone.
Protein WatchdogsCells have helpers to keep proteins safely configured, and to dispose of proteins that can’t be fixed. These helpers, called chaperones, assist at the birth of proteins as they are made outside the nucleus and watch over their proper folding thereafter.
Another set of proteins, called heat shock factors, also work as part of a cell’s quality assurance system. The heat shock response is engaged when cells are stressed or when cells recognize that proteins are being damaged. Both the heat shock factors and chaperones act to decide whether a damaged protein can be refolded, and if not, to consign to a cellular trash heap, cell components called proteosomes.
These common, and ancient, mechanism for cells to guard the integrity of their proteins explains why such simple creatures as a worm with fewer than a thousand cells can serve as a screen for ALS therapeutics. All animal cells watch out for protein damage, and all animal cells have retained ways to fix such problems.
Hours to a WormAnother advantage to the worm model is that scientists can rapidly create a transgenic worm. Researchers can insert a gene to create a transgenic worm in a matter of hours, due to the worm’s three day life span. A transgenic mouse by contrast takes months to make. Morimoto’s team has already investigated a number of transgenic worms that bear different mutations of the human SOD1 gene. Some of these worms show visible aggregates of the mutant SOD1, depending on which mutation they express.
The worms also show a convenient property of the aggregated SOD1. Lowering the temperature at which the worms live can prevent the aggregation. Raising the temperature from 20 degrees to 25 degrees Celsius makes some of the transgenics move sluggishly. Such a simple manipulation of the environment can aid in screens for potential therapeutics. Any molecule that would stop the aggregation or reverse the sluggishness stands a good chance of affecting the disease process.
Treating ALSSo far, the Morimoto team has found 80 different genes that increase quality control by activating the chaperones in the worm’s cells. The researchers are starting to screen for small molecules on the way to developing new ALS treatments. With further research, the worm with SOD1 mutations will undoubtedly prove invaluable in the search for new ALS therapeutics.
