These man-made molecules also were effective against the abnormal protein that causes Machado-Joseph disease, a neurological condition similar to Huntington’s.
The researchers’ approach relies on interfering with the steps by which genetic information in cells is “translated” from DNA to make proteins, which carry out vital biological functions.
Huntington’s and Machado-Joseph are fatal inherited diseases caused by abnormal repeats of a small segment in a person’s DNA, or genetic code, represented by the letters CAG. These mutations result in the body producing malfunctioning proteins that cause the diseases. The more repeats, the worse the disease, and the earlier in life it appears. A person with the disease carries one normal copy of the gene and one mutated copy in his or her cells.
In Huntington’s, this CAG repeat occurs in a gene called huntingtin, and in Machado-Joseph, it occurs in a gene called ataxin-3. A person with Huntington’s can have up to 100 CAG repeats. CAG repeats are involved in several other neurodegenerative diseases, including Fragile X syndrome, the most common form of mental retardation, and myotonic dystrophy.
While these genes are best known for the devastating effects of their mutated forms, their normal forms are essential for embryonic development, nerve function and other bodily processes. Any treatment that interferes with the mutant forms must leave the normal forms as unaffected as possible, Dr. Corey said.
“Attempting to intervene is very risky, but because the problem is important, it’s worth doing,” he said.
In the current study, the researchers created short lengths of molecules that resemble ribonucleic acid (RNA), the chemical cousin of DNA. These mimics, called PNAs and LNAs, were specifically designed to bind to CAG repeats, preventing cells from creating the abnormal proteins. The researchers also designed short lengths of RNA called small interfering RNA, or siRNA, to interfere with CAG repeats.
In cells from Huntington’s patients, the PNAs, LNAs and siRNAs decreased the amount of mutant protein produced, in some cases up to 100 percent. The effect was greatest when the compounds interfered with long lengths of CAG repeats; the effectiveness varied, however, among cells taken from different patients.
Some forms of these compounds left the normal forms of huntingtin and ataxin-3 proteins undisturbed, but other compounds partly or completely blocked their formation. In some cells, some of the RNA mimics drastically cut the production of both mutant and normal proteins – an undesirable effect, Dr. Corey said.
These findings indicate that further tweaking of the molecular structures of the RNA mimics will be needed to minimize the effects on normal proteins.
“It is encouraging that small chemical changes could substantially enhance selectivity,” Dr. Corey said. “If we can test a handful of compounds and identify better ones, we have reason to believe that more testing will continue to produce significant improvement.”
Because this study was done in cultured cells, and not in whole animals or humans, it does not indicate how much of the abnormal proteins must be blocked to treat the disease effectively, he said. “Fifty percent inhibition might be enough, but that remains to be determined,” Dr. Corey said.
In future studies, the researchers plan to try these RNA mimics in whole animals, using several different mutations of the genes.
Laurie Tompkins, who oversees neurogenetics grants at the National Institutes of Health’s National Institute of General Medical Sciences, said the ability to control individual genes makes this work stand out.
“By exploiting processes that occur in normal cells, Dr. Corey has come up with a clever way to do this that may well lead to new ways to combat Huntington’s and other related diseases,” she said.
Other UT Southwestern researchers from the Department of Pharmacology involved in the study were co-lead authors Dr. Jiaxin Hu, assistant instructor, and Dr. Masayuki Matsui, postdoctoral researcher; Dr. Keith Gagnon, postdoctoral researcher; and graduate student Jacob Schwartz; Dr. Jun Wu, assistant instructor in physiology; and Dr. Ilya Bezprozvanny, professor of physiology, also participated, as did researchers from Sigma-Aldrich Genopole Campus in France.
The study was funded by the High-Q Foundation, the National Institutes of Health, the Welch Foundation and the Ataxia MJD Research Project Inc.
Aline McKenzie | EurekAlert!
Further reports about: > CAG > DNA > Huntington's disease > LNAs > Machado-Joseph disease > Medical Wellness > PNAS > RNA > Small Molecule > abnormal protein > bodily processes > fragile X syndrome > human cells > man-made molecules > mental retardation > molecular structure > mutant protein production > myotonic dystrophy > neurodegenerative disease > neurological condition > vital biological functions
'Y' a protein unicorn might matter in glaucoma
23.10.2017 | Georgia Institute of Technology
Microfluidics probe 'cholesterol' of the oil industry
23.10.2017 | Rice University
Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
23.10.2017 | Event News
17.10.2017 | Event News
10.10.2017 | Event News
23.10.2017 | Life Sciences
23.10.2017 | Physics and Astronomy
23.10.2017 | Health and Medicine